Cancers

25 pages, 1351 KB

Open AccessSystematic Review

Unlocking the Potential of Immune Checkpoint Inhibitors in HR+/HER2− Breast Cancer: A Systematic Review

by Giuseppe Di Grazia, Arianna Dri, Angela Grieco, Claudia Martinelli, Michela Palleschi, Federica Martorana, Giacomo Barchiesi, Grazia Arpino, Carmine De Angelis, Michelino De Laurentiis, Lucia Del Mastro, Fabio Puglisi, Paolo Vigneri and Mario Giuliano

Cancers 2025, 17(17), 2940; https://doi.org/10.3390/cancers17172940 - 8 Sep 2025

Viewed by 664

Abstract

Background: Hormone-receptor-positive (HR+)/HER2-negative (HER2−) breast cancer (BC) is characterized by low immunogenicity and an immunosuppressive microenvironment. These features likely contribute to the inconsistent clinical activity of immune checkpoint inhibitors (ICIs) in this BC subtype. We conducted a systematic review of clinical trials evaluating [...] Read more.

Background: Hormone-receptor-positive (HR+)/HER2-negative (HER2−) breast cancer (BC) is characterized by low immunogenicity and an immunosuppressive microenvironment. These features likely contribute to the inconsistent clinical activity of immune checkpoint inhibitors (ICIs) in this BC subtype. We conducted a systematic review of clinical trials evaluating ICIs in HR+/HER2− BC patients, focusing on potential biomarkers of response and resistance to these drugs. Methods: We systematically searched in Medline via PubMed, EMBASE, and CENTRAL for phase II/III clinical trials published between 2013 and 2023, testing ICIs alone or in combination with other agents in HR+/HER2− BC patients at any stage. All the searches were performed up to 27 January 2024. Data on study characteristics, clinical outcomes, and biomarker profiles were extracted, and due to study heterogeneity, a narrative synthesis was performed, without risk-of-bias assessment or meta-analysis. Results: Twenty-five studies were included, with 3298 patients enrolled overall. Eighteen of these trials enrolled patients with advanced disease. All trials investigated ICI combination regimens, more frequently with chemotherapy, CDK4/6 inhibitors, or other immunotherapeutic agents. Most of the studies enrolling patients with advanced disease failed to show a significant clinical activity of ICIs. In the early setting, neoadjuvant chemo-immunotherapy with nivolumab or pembrolizumab increased the rate of complete responses compared to chemotherapy alone. Moreover, high programmed death-ligand 1 (PD-L1) expression, low ER (estrogen receptor), and high tumor-infiltrating lymphocyte (TIL) levels correlated with improved outcomes. Consistently, markers indicating enhanced immune activation, such as the MammaPrint High 2 (MP2) genomic signature, were associated with increased ICI sensitivity. Discussion: Despite the limited overall efficacy, ICIs may represent a viable therapeutic option for a selected subset of HR+/HER2− BC patients. However, this systematic review is limited by study heterogeneity and the inclusion of ongoing or immature trials, which prevents quantitative analysis and may affect future conclusions on ICIs in HR+/HER2− breast cancer. Finally, optimized combination strategies could enhance tumor immunogenicity, while predictive biomarkers such as PD-L1, TILs, or specific genomic signatures could identify responsive patients. Full article

(This article belongs to the Special Issue Navigating the Landscape of Female Cancers: Recent Discoveries and Treatment Trends)

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11 pages, 794 KB

Open AccessArticle

Identifying the Need for Prehabilitation in Cancer Patients Undergoing Nephrectomy or Nephroureterectomy

by Bente Thoft Jensen, Peter Blak Hjort, Kathrine Melchiorsen, Henriette Vind Thaysen, Ida Larsen, Mai Lorenzen, Rikke Knudsen and Anna K. Keller

Cancers 2025, 17(17), 2939; https://doi.org/10.3390/cancers17172939 - 8 Sep 2025

Viewed by 397

Abstract

Background: The potential benefits of prehabilitation in patients undergoing surgery for renal cell carcinoma (RCC) or upper-tract urothelial carcinoma (UTUC) remain unknown. The aim was to evaluate physical function and baseline characteristics over the course of treatment to identify a potential need for [...] Read more.

Background: The potential benefits of prehabilitation in patients undergoing surgery for renal cell carcinoma (RCC) or upper-tract urothelial carcinoma (UTUC) remain unknown. The aim was to evaluate physical function and baseline characteristics over the course of treatment to identify a potential need for prehabilitation. Methods: In this prospective observational study, 62 patients were enrolled—31 undergoing nephrectomies for RCC and 31 undergoing nephroureterectomy for UTUC. Baseline assessments included nutritional screening (NRS 2002), frailty (Clinical Frailty Scale), hemoglobin and iron levels, smoking status, and physical function using the Six-Minute Walk Test (6MWT) and the 30-Second Sit-to-Stand Test (30STS). Functional tests were repeated at hospital discharge and at two-week postoperative follow-up visit. Results: At baseline, 45% of RCC and 68% of UTUC patients were at nutritional risk. Preoperative frailty was present in 20% of the cohort, and 53% had anemia. Functional impairment below the lower limit values (LLVs) was observed in 16% for the RCC and 36% of the UTUC, assessed by 6MWT. The 30 STS revealed that 58% of RCC and 42% of UTUC were below LLV. At discharge, impairment peaked, with 59% and 82% of patients being below the LLVs, respectively. Functional performance partially recovered at follow-up but did not return to baseline levels. Conclusions: Preoperative nutritional deficits, anemia, and functional impairment are prevalent in patients undergoing nephrectomy or nephroureterectomy. A marked postoperative functional decline was identified postoperatively supporting a potential need for early individualized prehabilitation strategies to improve recovery in patients undergoing kidney cancer surgery. Full article

(This article belongs to the Special Issue Clinical Treatment and Prognostic Factors of Urologic Cancer)

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44 pages, 2570 KB

Open AccessReview

The Underlying Mechanisms and Emerging Strategies to Overcome Resistance in Breast Cancer

by Krishnaswamy Kannan, Alagarsamy Srinivasan, Aarthi Kannan and Nawab Ali

Cancers 2025, 17(17), 2938; https://doi.org/10.3390/cancers17172938 - 8 Sep 2025

Viewed by 1134

Abstract

Despite advances in early detection and targeted therapies, breast cancer (BC) remains a leading cause of cancer-related mortality among women worldwide. Resistance develops through the interplay of tumor-intrinsic heterogeneity and tumor-extrinsic influences, including the tumor microenvironment and immune–metabolic interactions. This complexity drives therapeutic [...] Read more.

Despite advances in early detection and targeted therapies, breast cancer (BC) remains a leading cause of cancer-related mortality among women worldwide. Resistance develops through the interplay of tumor-intrinsic heterogeneity and tumor-extrinsic influences, including the tumor microenvironment and immune–metabolic interactions. This complexity drives therapeutic evasion, metastatic progression, and poor outcomes. Resistance mechanisms include drug efflux, genetic mutations, and altered signaling pathways. Additional contributors are cancer stem cell plasticity, exosomal RNA transfer, stromal remodeling, epigenetic alterations, and metabolic reprogramming. Microbial influences and immune evasion further reduce treatment effectiveness. Collectively, these processes converge on regulated cell death (RCD) pathways—apoptosis, ferroptosis, and pyroptosis—where metabolic shifts and immune suppression recalibrate cell death thresholds. Nutrient competition, hypoxia-driven signaling, and lactate accumulation weaken antitumor immunity and reinforce resistance niches. In this review, we synthesize the genetic, metabolic, epigenetic, immunological, and microenvironmental drivers of BC resistance within a unified framework. We highlight the convergence of these mechanisms on RCD and immune–metabolic signaling as central principles. Artificial intelligence (AI) is emphasized as a cross-cutting connector that links major domains of resistance biology. AI supports early detection through ctDNA and imaging, predicts efflux- and mutation-driven resistance, models apoptotic and ferroptotic vulnerabilities, and stratifies high-risk patients such as TNBC patients. Full article

(This article belongs to the Special Issue Genetics and Epigenetics of Gynecological Cancer)

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Graphical abstract

16 pages, 3377 KB

Open AccessArticle

Feasibility of Anti-CEA Dye Conjugate for Cancer-Specific Imaging in Gastric Cancer Cell Lines and Mouse Xenograft Models

by Kyoungyun Jeong, Annie Eunhee Koo, Jaeun Yoo, Ji-Yeon Shin, Leena Lim, Hyun Myong Kim, Ji-Yong Park, Yun-Sang Lee, Yoon-Jin Kwak, Hye Seung Lee, Yie-Ri Yoo, Bérénice Framery, Karen Dumas, Françoise Cailler, André Pèlegrin, Do-Joong Park, Han-Kwang Yang, Seong-Ho Kong and Hyuk-Joon Lee

Cancers 2025, 17(17), 2937; https://doi.org/10.3390/cancers17172937 - 8 Sep 2025

Viewed by 539

Abstract

Purpose: Near-infrared fluorescence-guided surgery (FGS) using cancer-specific tracers is promising for tailored gastric cancer (GC) surgery. Carcinoembryonic antigen (CEA) is a potential target due to its high expression in various digestive cancers, including GC. Materials and Methods: SGM-101, a chimeric anti-CEA monoclonal antibody [...] Read more.

Purpose: Near-infrared fluorescence-guided surgery (FGS) using cancer-specific tracers is promising for tailored gastric cancer (GC) surgery. Carcinoembryonic antigen (CEA) is a potential target due to its high expression in various digestive cancers, including GC. Materials and Methods: SGM-101, a chimeric anti-CEA monoclonal antibody conjugated with the near-infrared dye BM-104, was evaluated in GC. CEA expression was identified in GC cell lines at the mRNA and protein levels. Xenograft models (MKN-45, SNU-16, SNU-668, 85As2mLuc) were established in mice and injected with SGM-101 or PBS. Biodistribution was monitored using in vivo fluorescence imaging. Tumors were further analyzed by immunofluorescence. In a peritoneal carcinomatosis model, 85As2mLuc cells were injected intraperitoneally, and tumors were evaluated by bioluminescence and fluorescence and histology. Results: MKN-45, SNU-16, and 85As2mLuc were CEA-positive, while SNU-668 was CEA-negative. Flow cytometry confirmed CEA expression: MKN-45 (98%), SNU-16 (85.6%), SNU-668 (6.42%) and 85As2mLuc (78.4%). SGM-101 selectively targeted CEA-expressing tumors, with fluorescence peaking at 48 h, and immunofluorescence verified localization in tumor cells. In the peritoneal models, SGM-101 enabled precise detection of CEA-positive tumors. Conclusions: This study provides the first evidence for the feasibility of SGM-101 in gastric cancer, demonstrating its novelty and translational potential as a cancer-specific imaging agent for fluorescence-guided surgery. Full article

(This article belongs to the Section Methods and Technologies Development)

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11 pages, 4595 KB

Open AccessArticle

Computed Tomography of Neoplastic Infiltrating Renal Masses in Patients Without a Previous History of Cancer

by Carlos Nicolau, Andreu Ivars, Carmen Sebastia, Clara Bassaganyas, María Fresno, Leonardo Rodríguez, Josep Puig, Marc Comas-Cufí and Blanca Paño

Cancers 2025, 17(17), 2936; https://doi.org/10.3390/cancers17172936 - 8 Sep 2025

Viewed by 447

Abstract

Background/Objectives: Infiltrative renal masses, characterized by ill-defined margins and parenchymal invasion without forming a discrete mass, present a diagnostic challenge, particularly in patients without a prior history of malignancy. Differentiating among the most common malignant etiologies—renal cell carcinoma (RCC), urothelial carcinoma (UC), and [...] Read more.

Background/Objectives: Infiltrative renal masses, characterized by ill-defined margins and parenchymal invasion without forming a discrete mass, present a diagnostic challenge, particularly in patients without a prior history of malignancy. Differentiating among the most common malignant etiologies—renal cell carcinoma (RCC), urothelial carcinoma (UC), and lymphoma—is essential for guiding appropriate treatment. This study aimed to evaluate whether specific computed tomography (CT) features can assist in the differential diagnosis of these lesions. Methods: A retrospective review was conducted on 68 patients with infiltrative renal masses presented at a tertiary hospital’s oncologic urology committee between 2018 and 2022. Patients with prior malignancy or signs of infection were excluded. All cases underwent contrast-enhanced CT within three months of diagnosis and had histopathological confirmation. Imaging features such as necrosis, collecting system involvement, lymphadenopathy, and others were assessed and statistically analyzed. Results: RCC was the most frequent diagnosis (68%), followed by UC (18%) and lymphoma (7.4%). Significant differences were observed in imaging features: necrosis was more common in RCC (87%) than in UC (25%) and lymphoma (20%), p < 0.001; collecting system involvement was universal in UC (100%) and less common in RCC (65%) and lymphoma (40%), p = 0.009; and lymphadenopathy was more frequent in lymphoma (80%) than in UC (67%) and RCC (35%), p = 0.038. Tumor size also varied significantly, with lymphomas presenting the largest median size (11 cm), followed by RCCs (8.2 cm) and UCs (5 cm), p < 0.001. Conclusions: CT imaging features, particularly necrosis, collecting system involvement, and lymphadenopathy, can aid in distinguishing among RCC, UC, and lymphoma in patients with infiltrative renal masses and no prior cancer history. These findings may support more accurate diagnoses and inform tailored therapeutic strategies. Full article

(This article belongs to the Section Methods and Technologies Development)

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18 pages, 3960 KB

Open AccessArticle

Machine Learning Uncovers Novel Predictors of Peptide Receptor Radionuclide Therapy Eligibility in Neuroendocrine Neoplasms

by Gábor Sipka, István Farkas, Annamária Bakos, Anikó Maráz, Zsófia Sára Mikó, Tamás Czékus, Mátyás Bukva, Szabolcs Urbán, László Pávics and Zsuzsanna Besenyi

Cancers 2025, 17(17), 2935; https://doi.org/10.3390/cancers17172935 - 8 Sep 2025

Viewed by 572

Abstract

Background: Neuroendocrine neoplasms (NENs) are a diverse group of malignancies in which somatostatin receptor expression can be crucial in guiding therapy. We aimed to evaluate the effectiveness of [^99mTc]Tc-EDDA/HYNIC-TOC SPECT/CT in differentiating neuroendocrine tumor histology, selecting candidates for radioligand therapy, and [...] Read more.

Background: Neuroendocrine neoplasms (NENs) are a diverse group of malignancies in which somatostatin receptor expression can be crucial in guiding therapy. We aimed to evaluate the effectiveness of [^99mTc]Tc-EDDA/HYNIC-TOC SPECT/CT in differentiating neuroendocrine tumor histology, selecting candidates for radioligand therapy, and identifying correlations between somatostatin receptor expression and non-imaging parameters in metastatic NENs. Methods: This retrospective study included 65 patients (29 women, 36 men, mean age 61) with metastatic neuroendocrine neoplasms confirmed by histology, follow-up, or imaging, comprising 14 poorly differentiated carcinomas and 51 well-differentiated tumors. Somatostatin receptor SPECT/CT results were assessed visually and semiquantitatively, with mathematical models incorporating histological, oncological, immunohistochemical, and laboratory parameters, followed by biostatistical analysis. Results: Of 392 lesions evaluated, the majority were metastases in the liver, lymph nodes, and bones. Mathematical models estimated somatostatin receptor expression accurately (70–83%) based on clinical parameters alone. Key factors included tumor origin, oncological treatments, and the immunohistochemical marker CK7. Associations were found between age, grade, disease extent, and markers (CEA, CA19-9, AFP). Conclusions: Our findings suggest that [^99mTc]Tc-EDDA/HYNIC-TOC SPECT/CT effectively evaluates somatostatin receptor expression in NENs. Certain immunohistochemical and laboratory parameters, beyond recognized factors, show potential prognostic value, supporting individualized treatment strategies. Full article

(This article belongs to the Special Issue Mathematical Oncology: Using Mathematics to Enable Cancer Discoveries)

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12 pages, 685 KB

Open AccessArticle

The Role of Perceived Benefits in Buffering Gastrointestinal-Symptom Burden Among Post-Operative Colorectal Cancer Patients: A Six-Month Longitudinal Study

by Ming-Wei Chang, Ashley Wei-Ting Wang and Cheng-Shyong Chang

Cancers 2025, 17(17), 2934; https://doi.org/10.3390/cancers17172934 - 8 Sep 2025

Viewed by 434

Abstract

Objectives: The goal of this longitudinal study was to explore how gastrointestinal-symptom distress and benefit finding together influence health-related quality of life (HRQOL) over time in colorectal cancer (CRC) survivors. Colorectal cancer (CRC) survivorship may differ from other cancer types due to the [...] Read more.

Objectives: The goal of this longitudinal study was to explore how gastrointestinal-symptom distress and benefit finding together influence health-related quality of life (HRQOL) over time in colorectal cancer (CRC) survivors. Colorectal cancer (CRC) survivorship may differ from other cancer types due to the persistent burden of gastrointestinal symptoms. The highly visible and socially sensitive nature of these sequelae may influence the trajectory of benefit finding compared with other cancers. Specifically, we explored whether increases in symptom distress predicted declines in physical and mental HRQOL whether benefit finding was directly related to or buffered the negative impact of symptom distress on HRQOL. Methods: Participants were 73 Taiwanese women and men who underwent surgery for CRC. Using a three-time-point, multilevel framework, participants were assessed at 1, 3, and 6 months after surgery. Hierarchical linear modeling was used to investigate whether gastrointestinal-symptom distress and benefit finding covary over time with HRQOL. Results: The results indicated that increases in gastrointestinal-symptom distress were linked to declines in both physical and mental HRQOL. Benefit finding had no direct association with HRQOL but significantly moderated the symptom-HRQOL relationship, weakening the negative impact of symptom distress among those with higher benefit finding. Conclusions: Rises in a CRC survivor’s gastrointestinal-symptom distress went hand-in-hand with drops in both physical and mental HRQOL. This study adds to the literature in that benefit finding has a favorable effect on cancer adjustment when patients face higher symptom distress after the surgery and treatment. Further implications on possible mechanisms were discussed. Full article

(This article belongs to the Special Issue Medical Complications and Supportive Care in Patients with Cancer (2nd Edition))

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14 pages, 2751 KB

Open AccessArticle

Bone Targeted Parathyroid Hormone Antagonists for Prevention of Breast Cancer Bone Metastases

by Muralidharan Anbalagan, Tulasi Ponnapakkam, Binghao Zou, Jarvis Williams, Fouad Saeg, Matthew E. Burow, Robert C. Gensure and Brian G. Rowan

Cancers 2025, 17(17), 2933; https://doi.org/10.3390/cancers17172933 - 8 Sep 2025

Viewed by 558

Abstract

Background/Objectives: Advanced breast cancer patients may develop bone metastases, leading to severe pain, fractures, and mortality. Current treatments have limited efficacy, necessitating targeted therapy approaches. Bone metastatic breast cancer cells secrete PTHrP that promotes tumor growth and bone degradation. Previous PTH/PTHrP antagonists failed [...] Read more.

Background/Objectives: Advanced breast cancer patients may develop bone metastases, leading to severe pain, fractures, and mortality. Current treatments have limited efficacy, necessitating targeted therapy approaches. Bone metastatic breast cancer cells secrete PTHrP that promotes tumor growth and bone degradation. Previous PTH/PTHrP antagonists failed clinically due to short half-life and insufficient bone targeting. The present study evaluated the following two novel bone-targeted PTH antagonists fused to a collagen-binding domain (CBD) for enhanced bone localization: PTH(7-33)-CBD and [W2]PTH(1-33)-CBD. Methods: Intra-tibial and intra-iliac breast tumor models in mice were used to evaluate drug efficacy in reducing tumor burden and bone destruction. Results: Bioluminescent imaging, X-ray, and micro-CT analysis revealed that both drugs significantly reduced tumor burden and osteolysis compared to control, with [W2]PTH(1-33)-CBD additionally improving trabecular bone structure. Drug efficacy was confirmed in both intra-tibial and intra-iliac breast tumor models. Conclusions: These findings identify CBD-fused PTH/PTHrP antagonists as a promising therapeutic strategy for breast cancer bone metastases. Full article

(This article belongs to the Special Issue Cell Migration and Invasion in Cancer)

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18 pages, 2698 KB

Open AccessArticle

A Novel Nuclear-Localized Micropeptide, MP60, Promotes Hepatocellular Carcinoma Progression via the Epithelial-Mesenchymal Transition

by Chencheng Li, Xiu Hong, Sarra Setrerrahmane, Xiaoyi Sun, Xue Zhang and Hanmei Xu

Cancers 2025, 17(17), 2932; https://doi.org/10.3390/cancers17172932 - 7 Sep 2025

Viewed by 778

Abstract

Background: Micropeptides, encoded by non-coding RNAs, play a pivotal role in various cellular functions. While several micropeptides have already been linked to HCC, their roles remain incompletely understood. Our study identifies MP60, a conserved micropeptide strongly associated with HCC progression. Methods and Results: [...] Read more.

Background: Micropeptides, encoded by non-coding RNAs, play a pivotal role in various cellular functions. While several micropeptides have already been linked to HCC, their roles remain incompletely understood. Our study identifies MP60, a conserved micropeptide strongly associated with HCC progression. Methods and Results: By analyzing The Cancer Genome Atlas (TCGA) dataset, we assessed the coding potential of long non-coding RNAs (lncRNAs) with significant expression changes in HCC. Our findings reveal that ENST0000614292, a transcript of LINC01138, exhibited the highest coding potential, encoding a putative 60-amino-acid micropeptide, which we have named MP60 and confirmed the expression of MP60 in HCC tissues, with a nuclear localization. MP60 directly interacts with RNA-binding motif protein 10 (RBM10) and downregulates its expression. Additionally, MP60 modulates EMT. Functional analyses demonstrated that MP60 promotes cellular proliferation and migration, while reducing cellular adhesion, translated by enhanced tumorigenesis in vivo. Notably, MP60 expression is markedly increased in HCC tissues and is associated with a poorer prognosis. Conclusions: These findings identify MP60 as a potential biomarker and therapeutic target in HCC, linking its oncogenic effects to EMT modulation and tumor progression. Full article

(This article belongs to the Section Molecular Cancer Biology)

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30 pages, 2658 KB

Open AccessReview

Targeting Oncogenic Activity and Signalling of Mutant Receptor Tyrosine Kinase FLT3

by Boban Dobrevski, Hannah Willems, Carolin Lossius-Cott and Jörg P. Müller

Cancers 2025, 17(17), 2931; https://doi.org/10.3390/cancers17172931 - 7 Sep 2025

Viewed by 1335

Abstract

Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) that is involved in cell survival, proliferation, and differentiation of haematopoietic progenitors of lymphoid and myeloid lineages. Oncogenic mutations in the FLT3 gene, resulting in constitutively active FLT3 variants, are frequently found [...] Read more.

Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase (RTK) that is involved in cell survival, proliferation, and differentiation of haematopoietic progenitors of lymphoid and myeloid lineages. Oncogenic mutations in the FLT3 gene, resulting in constitutively active FLT3 variants, are frequently found in patients with acute myeloid leukaemia (AML). In particular, patients expressing FLT3 ITD (internal tandem duplications of the juxtamembrane domain of FLT3) correlate with poor patient survival. Targeting FLT3-mutated leukaemic stem cells is therefore a key to the efficient treatment of patients with relapsed/refractory AML. The efficacy of approved tyrosine kinase inhibitors is regularly compromised by various resistance pathways or secondary mutations. Based on the current molecular understanding of aberrant signal transduction pathways and cell transformation, novel alternative treatment approaches can be exploited for therapeutic purposes. In particular, new insights into the regulation of the activity of counteracting protein tyrosine phosphatases (PTPs), the aberrant biogenesis and activation of mutant FLT3 proteins, as well as common factors controlling cell transformation are attractive avenues. This review summarises the current knowledge about the regulation of the oncogenic activities of mutant FLT3 proteins and discusses possible options for alternative treatments. Full article

(This article belongs to the Special Issue New Approaches to Biology and Treatment of Acute Leukemia)

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24 pages, 4173 KB

Open AccessArticle

The Effect of Lurbinectedin as a Monotherapy and in Combination with Ionizing Radiation on Sarcoma Cell Lines

by Hannah Alsheimer, Paula Schiller, Sabine Semrau, Felix Grabenbauer, Rainer Fietkau, Luitpold V. Distel and Laura S. Hildebrand

Cancers 2025, 17(17), 2930; https://doi.org/10.3390/cancers17172930 - 7 Sep 2025

Viewed by 770

Abstract

Background/Objectives: Soft tissue sarcomas are rare, heterogeneous tumors with limited therapeutic options and suboptimal outcomes in advanced stages. Lurbinectedin is a promising new antineoplastic alkylating agent. This study investigates its cytotoxic effects and its potential as a radiosensitizing agent on soft tissue sarcoma. [...] Read more.

Background/Objectives: Soft tissue sarcomas are rare, heterogeneous tumors with limited therapeutic options and suboptimal outcomes in advanced stages. Lurbinectedin is a promising new antineoplastic alkylating agent. This study investigates its cytotoxic effects and its potential as a radiosensitizing agent on soft tissue sarcoma. Methods: Four soft tissue sarcoma cell lines were treated with lurbinectedin alone or in combination with ionizing radiation. Single-dose irradiation in a 4-day protocol was compared with prolonged treatment and an additional fractionated ionizing radiation scheme in a 6-day protocol. Cellular responses were analyzed by flow cytometry for apoptosis (Annexin V)/necrosis (7AAD) and cell cycle (Hoechst), clonogenic cell survival, and scratch assays for cell migration. Results: In the 4-day protocol, lurbinectedin induced G2/M arrest in all cell lines (p = 0.029) and significantly increased apoptosis/necrosis (p = 0.029) in SW-872. Lurbinectedin-treatment resulted in a decrease (p ≤ 0.002) of clonogenic cells in all cell lines. In the scratch assay, cell migration was delayed in two cell lines (p = 0.048) after lurbinectedin-treatment. Additional radiotherapy had no significant effect compared to lurbinectedin-monotherapy in apoptosis/necrosis and G/2M arrest in the 4-day protocol, clonogenic cell assay, and scratch assay. In the 6-day protocol, lurbinectedin induced an increase (p = 0.029) in G2/M arrest in all cell lines and apoptosis/necrosis in three cell lines, while resulting in a decrease (p < 0.001) of clonogenic cells. Additional radiotherapy had a significant effect on the decrease in clonogenic cells (p ≤ 0.048) in two cell lines but did not increase G2/M arrest and apoptosis/necrosis. Conclusions: Lurbinectedin had strong effects on three of the selected cell lines by inducing G2/M arrest, promoting apoptosis/necrosis, and reducing clonogenic survival, suggesting that it may be a promising chemotherapeutic agent in soft tissue sarcoma treatment. The effect on the fourth cell line was limited, as well as the effect on cell migration. Single-dose irradiation occasionally interfered with the effects of Lurbinectedin, whereas adding fractionated irradiation caused an additional decrease in clonogenic survival, indicating that the combination of Lurbinectedin with fractionated ionizing radiation may have promising effects. Full article

(This article belongs to the Special Issue Radiotherapy for Sarcoma)

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18 pages, 2312 KB

Open AccessReview

Hodgkin Lymphoma Classification—From Historical Concepts to Current Refinements

by Antonino Carbone and Mohamed N. Alibrahim

Cancers 2025, 17(17), 2929; https://doi.org/10.3390/cancers17172929 - 7 Sep 2025

Viewed by 869

Abstract

The current classification of Hodgkin lymphoma (HL) is the result of an integrated approach that combines the evaluation of morphological patterns, immunophenotypic characteristics, molecular features, and clinical presentation. Evolving from its origins based solely on histological observation to the latest updates in the [...] Read more.

The current classification of Hodgkin lymphoma (HL) is the result of an integrated approach that combines the evaluation of morphological patterns, immunophenotypic characteristics, molecular features, and clinical presentation. Evolving from its origins based solely on histological observation to the latest updates in the WHO 5th Edition, this system has become an essential tool for accurate diagnosis and personalized therapeutic strategies. Each subtype of classic HL (cHL)—nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted—exhibits distinctive pathological and clinical features, now better understood through multidisciplinary studies and international collaborations. HL also includes nodular lymphocyte-predominant HL (NLPHL), a distinct entity with unique morphologic, immunophenotypic, and clinical features. A hallmark morphological feature of cHL is the presence of Hodgkin and Reed-Sternberg (HRS) cells, large and often multinucleated cells derived from B lymphocytes that have lost their typical B-cell phenotype. Identifying these cells is critical for diagnosis and for differentiating HL from other hematologic malignancies. HL is characterized by the rarity of malignant cells, a high curability rate, and a rich immune cell microenvironment that is both shaped and exploited by the tumor. Understanding these core aspects paves the way for exploring the role of immunologic and genetic biomarkers in refining classification, enhancing diagnosis, improving prognostic assessment, and guiding therapy for patients with cHL. Full article

(This article belongs to the Special Issue Advances in Hodgkin Lymphoma (HL))

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19 pages, 5931 KB

Open AccessArticle

The RNA-Binding Protein RBMX Mediates the Immunosuppressive Microenvironment of Osteosarcoma by Regulating CD8⁺T Cells

by Yu Qiu, Chao Pu, Chengguang Wang and Zhengxue Quan

Cancers 2025, 17(17), 2928; https://doi.org/10.3390/cancers17172928 - 6 Sep 2025

Viewed by 1435

Abstract

Background: The progression of osteosarcoma is closely related to the immune microenvironment. Related studies have found that the RNA-binding motif protein, X-linked (RBMX), plays a regulatory role in modulating the biological characteristics of the tumor microenvironment (TME). However, its regulatory mechanism in osteosarcoma [...] Read more.

Background: The progression of osteosarcoma is closely related to the immune microenvironment. Related studies have found that the RNA-binding motif protein, X-linked (RBMX), plays a regulatory role in modulating the biological characteristics of the tumor microenvironment (TME). However, its regulatory mechanism in osteosarcoma remains unclear. Methods: In this study, the expression of RBMX in osteosarcoma was analyzed using the results of bulk and single-cell transcriptome sequencing of human osteosarcoma. The RBMX knockout cell line was constructed via lentivirus transfection. The mouse subcutaneous implantable tumor model and single-cell transcriptome sequencing analysis revealed the effects of RBMX on the osteosarcoma microenvironment, as verified via multiplex immunofluorescence, flow cytometry, and PCR experiments. Results: Using the TARGET database and multiplex immunofluorescence, we found that RBMX is highly expressed in human osteosarcoma and is associated with poor prognosis. The high expression of RBMX may mediate the immunosuppressive microenvironment of human osteosarcoma. In vitro cell experiments showed that knockout of RBMX significantly inhibited the proliferation of mouse osteosarcoma cells. Through single-cell transcriptome sequencing analysis of subcutaneous implantable tumors in mice, we determined that RBMX deletion substantially elevated the recruitment of cytotoxic CD8⁺T cells within the mouse TME, which was further verified through flow cytometry analysis. Cell coculture assay confirmed that knockout of RBMX significantly enhanced the cytotoxic activity of CD8⁺T cells. Finally, cell communication and in vitro experimental verification revealed that knocking out RBMX might enhance the infiltration of CD8⁺T cells by upregulating histocompatibility 2, K1, and K region (H2-K1) and downregulating thrombospondin 1 (THBS1). Conclusions: This study may provide potential targets for reshaping the immune microenvironment of osteosarcoma and improving its therapeutic efficacy. Full article

(This article belongs to the Topic The Tumor Microenvironment, Immuno-Oncology, and Immune Checkpoint: Implications for Current and Emergent Immunotherapies, 2nd Edition)

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Graphical abstract

15 pages, 3262 KB

Open AccessArticle

Comparison of a Multi-Scenario Robustness Evaluation Method with Measurements for Proton Teletherapy

by Qiangxing Yang, Michael F. Moyers and Zhuangming Shen

Cancers 2025, 17(17), 2927; https://doi.org/10.3390/cancers17172927 - 6 Sep 2025

Viewed by 1458

Abstract

Background/Objectives: Multi-scenario calculational methods have been used to evaluate proton teletherapy plan robustness but few studies have been performed to determine the accuracy of these calculational methods. This study evaluates a multi-scenario method by comparing calculations to measurements made in phantoms that [...] Read more.

Background/Objectives: Multi-scenario calculational methods have been used to evaluate proton teletherapy plan robustness but few studies have been performed to determine the accuracy of these calculational methods. This study evaluates a multi-scenario method by comparing calculations to measurements made in phantoms that simulate the effects of possible uncertainties. Methods: Plans were made using four phantoms in which the delivered dose was highly sensitive to positional and penetration uncertainties. The effects of alignment and penetration uncertainties on the dose distributions of each of those phantoms were simulated by performing calculations using nine different uncertainty scenarios and comparing the calculations to measurements with induced physical alignment displacements. Measured dose distributions were obtained by exposing films placed inside the phantoms and extracting multiple linear profiles. The maximum and minimum doses obtained for each of the calculational scenarios were compared with the measured dose profiles. In addition, comparisons of DVHs for nominal and uncertainty scenarios were performed. Results: The results showed that, under the influence of uncertainties, the minimum dose for the four phantoms decreased by more than 20 Gy, the V_95% coverage fluctuated by more than 10%, but the maximum dose parameter changed by less than 5 Gy. This was expected, as no margins for uncertainties were applied around the targets. The envelope bounded by the maximum and minimum possible calculated doses contained most of the measurements, although the shapes of the dose profiles displayed some mismatches for wedge and head phantoms. There were a few points where the measured maximum dose for bone and lung slab phantom cases was slightly higher than the maximum dose calculated from the nine scenarios. Conclusions: This study demonstrates that a nine-scenario method can adequately evaluate the robustness of simple mono-directional plans containing heterogeneities. Full article

(This article belongs to the Special Issue The Advance of Pencil Beam Scanning Proton Beam Therapy in Cancers)

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14 pages, 512 KB

Open AccessArticle

Dynamic Tumor Tracking (DTT) for Hepatocellular Carcinoma Using the Vero4DRT Gimbaled Linac Stereotactic Body Radiation Therapy (SBRT) System

by Ronan L. McDermott, Emma M. Dunne, Lok In Josephine Ma, Alanah M Bergman, Marie-Laure A. Camborde, Tania Karan, Ante Mestrovic, Emilie E. Carpentier, Mitchell C. C. Liu, Devin Schellenberg and Roy M. K. Ma

Cancers 2025, 17(17), 2926; https://doi.org/10.3390/cancers17172926 - 6 Sep 2025

Viewed by 1375

Abstract

Background/Objectives: Stereotactic body radiation therapy (SBRT) is a therapeutic option for hepatocellular carcinoma (HCC). This study reviewed outcomes and toxicities of SBRT for HCC using a gimbal-mounted linear accelerator and real-time monitoring system. Methods: A single-institution, retrospective review of SBRT for [...] Read more.

Background/Objectives: Stereotactic body radiation therapy (SBRT) is a therapeutic option for hepatocellular carcinoma (HCC). This study reviewed outcomes and toxicities of SBRT for HCC using a gimbal-mounted linear accelerator and real-time monitoring system. Methods: A single-institution, retrospective review of SBRT for HCC using DTT between January 2018 and December 2020 was undertaken. Endpoints included local control (LC) and overall survival (OS). Results: A total of 74 patients with 82 tumors treated were identified. Median follow-up was 40.8 months. LC at 1, 3, and 5 years was 89.6%, 71.0%, and 59.9%, respectively. Median time to local failure was not reached. Median OS was 41.3 months (95% CI 30.7–51.8 months). OS at 1, 3, and 5 years was 89.2%, 60.6%, and 33.9%, respectively. On UVA, GTV ≥ 30 cm³ (p = 0.038), and PTV ≥ 150 cm³ (p = 0.010) were associated with an absolute drop in platelet count by ≥50,000/mm³ within six weeks of SBRT, while prior focal liver treatment (p = 0.097) showed a trend toward significance. Underlying viral cirrhosis (p = 0.033), A6 or higher pre-SBRT Child–Pugh score (p = 0.010), and pre-SBRT platelet count <100,000/mm³ (p = 0.017) were significant for a rise in Child–Pugh score of 2 points or more, and the volume of liver-GTV <1000 cm³ (p = 0.093) approached significance. Conclusions: SBRT using DTT is an effective therapeutic option for selected patients with HCC, providing acceptable local control and toxicity. Full article

(This article belongs to the Special Issue Hepatocellular Carcinoma: Current Treatment Strategies for Advanced Disease and Recurrence: 2nd Edition)

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14 pages, 1611 KB

Open AccessArticle

Distinct Metabolomic and Lipoprotein Signatures in Gall Bladder Cancer Patients of Black African Ancestry

by John Devar, Nnenna Elebo, Ashna Makan, Ariel Pincus, Nicola Lahoud, Stefano Cacciatore, Geoffrey Candy, Martin Smith and Ekene Emmanuel Nweke

Cancers 2025, 17(17), 2925; https://doi.org/10.3390/cancers17172925 - 6 Sep 2025

Viewed by 643

Abstract

Background: Gall bladder cancer (GBC) is the most common biliary tract malignancy and is often diagnosed at advanced stages, partly due to the absence of reliable biomarkers and limited understanding of its biology in African populations. This study aimed to characterize the metabolomic [...] Read more.

Background: Gall bladder cancer (GBC) is the most common biliary tract malignancy and is often diagnosed at advanced stages, partly due to the absence of reliable biomarkers and limited understanding of its biology in African populations. This study aimed to characterize the metabolomic and lipoprotein profiles of GBC patients of Black African ancestry. Methods: NMR spectroscopy was used to profile the serum samples. Group comparisons used Wilcoxon tests, correlations used Spearman’s rank test, unsupervised analysis was carried out using the KODAMA algorithm, partial least squares modeling estimated free cholesterol (FC) to cholesterol ester (CE) ratios, while multivariate logistic regression evaluated independent predictors. Results: GBC patients showed altered ethanol levels and dysregulated lipoproteins, including increased IDL-C, IDL-TG, and LDL-TG, and decreased HDL-C, HDL-P, and medium HDL-P. Total and conjugated bilirubin strongly correlated with lipoproteins. Unsupervised analysis revealed a GBC subgroup with abnormal lipoprotein profiles and elevated FC/CE ratios, suggesting cholestasis-related LpX formation. Elevated asparagine, reduced ethanol, and an inflammatory metabolic signature characterized the GBC fingerprint. Ethanol and bilirubin emerged as independent predictors of GBC. Conclusions: GBC patients exhibit distinct metabolomic and lipoprotein alterations that may underlie disease progression and serve as potential biomarkers. These findings enhance understanding of GBC pathophysiology in African populations and may inform future diagnostic strategies. Full article

(This article belongs to the Special Issue Unveiling the Complexity of Hepato-Biliary-Pancreatic Cancers: From Pathogenesis to Management)

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14 pages, 713 KB

Open AccessArticle

A Phase I Study of Carfilzomib with Cyclophosphamide and Etoposide in Relapsed and Refractory Leukemia and Solid Tumors

by Jessica Boklan, Anne-Marie Langevin, Kevin Bielamowicz, Kathleen Neville, Tanya Trippett, Valerie Brown, Steven G. DuBois, Francis Eshun, Jonathan Gelfond, Ativ Zomet, Aru Narendran and Norman J. Lacayo

Cancers 2025, 17(17), 2924; https://doi.org/10.3390/cancers17172924 - 6 Sep 2025

Viewed by 587

Abstract

Background: Novel therapies are needed for children, adolescents, and young adults with relapse/refractory leukemia or solid tumors. The proteasome inhibitor carfilzomib has demonstrated pre-clinical activity against several pediatric malignancies when used alone or in combination. Therefore, a multicenter dose-escalation phase 1 study of [...] Read more.

Background: Novel therapies are needed for children, adolescents, and young adults with relapse/refractory leukemia or solid tumors. The proteasome inhibitor carfilzomib has demonstrated pre-clinical activity against several pediatric malignancies when used alone or in combination. Therefore, a multicenter dose-escalation phase 1 study of carfilzomib administered in combination with cyclophosphamide and etoposide was conducted. Methods: Study eligibility included an age of 6 months to <30 years with relapsed/refractory leukemia (stratum A) or a relapsed/refractory non-CNS solid tumor (stratum B), Karnofsky/Lansky score ≥ 50, and adequate organ function. A 5-day regimen of cyclophosphamide 440 mg/m²/day, etoposide 100 mg/m²/day, and carfilzomib was administered every 28 days with growth factor support. The carfilzomib starting dose was 11 mg/m²/day, and dose escalation followed a rolling-six design, managed independently for each stratum. Dose-limiting toxicity (DLT) was assessed during the first cycle, and disease response was assessed after one cycle (stratum A) or two cycles (stratum B). Results: Thirty-eight patients were treated (14 in stratum A; 24 in stratum B). For stratum A, the maximum tolerated dose (MTD) for carfilzomib was 11 mg/m²/day. Three DLTs were observed: thrombocytopenia, pericarditis, and posterior reversible encephalopathy syndrome (PRES). Most patients received one cycle. For stratum B, an MTD was not reached. The highest dose level administered and recommended in phase 2 (RP2D) was 20 mg/m²/days 1–2 and 36 mg/m²/days 3–5 for cycle 1, then 36 mg/m² for days 1–5 of all subsequent cycles. There was a single DLT of PRES. A dose expansion for additional toxicity data was conducted. Overall, twenty patients received ≥ 2 cycles (range, 2–14). Conclusions: A 5-day schedule of carfilzomib/cyclophosphamide/etoposide was well-tolerated in patients with solid tumors. Patients with sarcomas benefited most, warranting further evaluation. Full article

(This article belongs to the Section Pediatric Oncology)

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13 pages, 1062 KB

Open AccessArticle

Impact of Intraoperative Lidocaine During Oncologic Lung Resection on Long-Term Outcomes in Primary Lung Cancer: A Post Hoc Analysis of a Randomized Controlled Trial

by Elena de la Fuente, Francisco de la Gala, Javier Hortal, Carlos Simón, Almudena Reyes, Lisa Rancan, Alberto Calvo, Angela Puig, Elena Vara, José María Bellón, Patricia Piñeiro and Ignacio Garutti

Cancers 2025, 17(17), 2923; https://doi.org/10.3390/cancers17172923 - 6 Sep 2025

Viewed by 522

Abstract

Background/Objectives: Lidocaine has demonstrated immunomodulatory properties and promising antitumor effects in experimental models, but its impact on long-term outcomes following oncologic surgery remains unclear. This study aimed to compare the impact of intraoperative lidocaine versus remifentanil on long-term cancer outcomes after primary [...] Read more.

Background/Objectives: Lidocaine has demonstrated immunomodulatory properties and promising antitumor effects in experimental models, but its impact on long-term outcomes following oncologic surgery remains unclear. This study aimed to compare the impact of intraoperative lidocaine versus remifentanil on long-term cancer outcomes after primary lung cancer surgery. Methods: This is a post hoc analysis of a randomized controlled trial (NCT03905837, EudraCT 2016-004271-52). From 154 patients who underwent elective lung resection via video-assisted thoracoscopic surgery (VATS) between January 2019 and June 2021 and were randomized to receive intraoperative lidocaine (intravenous or paravertebral) or remifentanil, we analyzed data from patients with confirmed primary lung cancer in the surgery specimen. Overall survival (OS) and disease-free survival (DFS) were assessed through May 2025. Survival outcomes were analyzed using Kaplan–Meier curves and log-rank tests. A multivariate Cox proportional hazards model was used to adjust for potential confounders. Results: Among the 97 patients with primary lung cancer finally included in the analysis, those in the lidocaine group exhibited improved OS compared with those who received intravenous remifentanil (log-rank p = 0.022). This association remained significant in the multivariate Cox regression analysis (HR 2.59, 95% CI 1.13–5.96, p = 0.025). No significant differences were observed in DFS overall (log-rank p = 0.283) or in DFS limited to recurrences of cancers present at the time of surgery, either the resected primary tumor or a prior malignancy (log-rank p = 0.080). Conclusions: In this post hoc analysis, lidocaine administration during oncologic lung resection was associated with improved OS in primary lung cancer patients. No differences in DFS were observed between groups; however, a non-significant trend toward improved DFS in lidocaine patients was noted when focusing on recurrences of cancers present at the time of surgery. Further investigation in larger prospective studies is warranted. Full article

(This article belongs to the Special Issue Perioperative Management and Cancer Outcome)

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26 pages, 1372 KB

Open AccessReview

Epithelial–Mesenchymal Transition in Osteosarcoma as a Key Driver of Pulmonary Metastasis

by Fangcheng Luo, Kosei Ando, Yoshinori Takemura, Tae-Hwi Park, Takafumi Yayama and Shinji Imai

Cancers 2025, 17(17), 2922; https://doi.org/10.3390/cancers17172922 - 6 Sep 2025

Viewed by 742

Abstract

Background: Osteosarcoma is an aggressive bone tumor with a high risk of lung metastasis, which severely affects patient survival. EMT plays a major role in tumor spread, therapy resistance, and cancer stemness. This review explores how EMT contributes to osteosarcoma metastasis and the [...] Read more.

Background: Osteosarcoma is an aggressive bone tumor with a high risk of lung metastasis, which severely affects patient survival. EMT plays a major role in tumor spread, therapy resistance, and cancer stemness. This review explores how EMT contributes to osteosarcoma metastasis and the underlying molecular mechanisms. Methods: We reviewed recent studies on EMT-related signaling pathways, transcription factors, and regulatory RNAs in osteosarcoma. We also examined the role of the tumor microenvironment. Results: EMT promotes cell detachment, migration, and lung colonization. Key pathways such as TGF-β, MAPK, PI3K/Akt, STAT3, Notch, and Wnt/β-catenin are involved. Non-coding RNAs further regulate EMT by interacting with these pathways. The tumor microenvironment, including hypoxia and immune cells, also supports EMT and metastasis. Conclusions: EMT is a key driver of metastasis and poor outcomes in osteosarcoma. Targeting EMT and its regulators may help prevent lung spread and improve treatment. Future strategies combining EMT inhibition with existing therapies could be promising for clinical application. Full article

(This article belongs to the Special Issue State of the Art and Novelties in Multidisciplinary Approach to Soft Tissue and Bone Sarcomas)

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22 pages, 3460 KB

Open AccessReview

An Update on Single-Cell RNA Sequencing in Illuminating Disease Mechanisms of Cutaneous T-Cell Lymphoma

by Sara Suhl, Alexander Kaminsky, Caroline Chen, Brigit A. Lapolla, Maggie H. Zhou, Joshua Kent, Abigail Marx, Ikenna David Nebo, Geat Ramush, Sophia Luyten, Yoni Sacknovitz, Julie Sung, Christina M. Bear, Celine M. Schreidah, Alejandro Gru and Larisa J. Geskin

Cancers 2025, 17(17), 2921; https://doi.org/10.3390/cancers17172921 - 5 Sep 2025

Viewed by 662

Abstract

Cutaneous T-cell Lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin lymphomas that currently have an incompletely understood pathophysiology and several challenges in both diagnosis and management. Single-cell RNA sequencing (scRNA-seq) is a powerful tool that enables the analysis of gene expression at the [...] Read more.

Cutaneous T-cell Lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin lymphomas that currently have an incompletely understood pathophysiology and several challenges in both diagnosis and management. Single-cell RNA sequencing (scRNA-seq) is a powerful tool that enables the analysis of gene expression at the individual-cell level, revealing cellular heterogeneity and a complex tumor microenvironment. As single-cell RNA sequencing has become increasingly utilized, we aimed to provide an update on recent notable applications of single-cell RNA sequencing in CTCL and their findings. The included studies highlight the intricate network of interactions in the tumor microenvironment that contributes to tumorigenesis. While CTCL is notoriously heterogeneous, our results identify key markers that prove promising for diagnosis, prognostication, and therapeutic targets. Full article

(This article belongs to the Special Issue Insights into the Pathogenesis of Cutaneous T-Cell Lymphoma and the Impact of These Potential Biomarkers on Future Diagnosis, Prognosis and Treatment)

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35 pages, 3592 KB

Open AccessReview

Melanoma Skin Cancer: A Comprehensive Review of Current Knowledge

by Camila Caraviello, Gianluca Nazzaro, Gianluca Tavoletti, Francesca Boggio, Nerina Denaro, Giulia Murgia, Emanuela Passoni, Valentina Benzecry Mancin and Angelo Valerio Marzano

Cancers 2025, 17(17), 2920; https://doi.org/10.3390/cancers17172920 - 5 Sep 2025

Viewed by 1155

Abstract

Cutaneous melanoma is the most severe form of skin cancer. The incidence of the disease has been increasing in the last decades, largely due to increased ultraviolet radiation exposure. A comprehensive understanding of the complex biological processes involved in melanoma development and progression [...] Read more.

Cutaneous melanoma is the most severe form of skin cancer. The incidence of the disease has been increasing in the last decades, largely due to increased ultraviolet radiation exposure. A comprehensive understanding of the complex biological processes involved in melanoma development and progression is essential for advancing patient care. Improvement in surveillance strategies, widespread use of sentinel lymph node biopsy, and breakthroughs in systemic therapy have all contributed considerably to enhancing patient outcomes and survival. Rapid advancements in melanoma management are expected to continue, particularly through innovations in molecular biology and genetics. These emerging technologies aim to enhance diagnostic accuracy, predict disease progression, and improve prognosis. Staying informed about these evolving developments is essential for professionals dealing with melanoma patients. This narrative review provides a comprehensive overview of the current state of cutaneous melanoma, covering fundamental areas, such as histopathology, genetics, epidemiology, diagnosis, and staging. It provides a foundation to enhance understanding of current treatment approaches and the principles behind emerging technologies. This review also highlights future directions in melanoma care, including improvements in neoadjuvant therapy, use of artificial intelligence-based algorithms, use of molecular biomarkers to improve diagnosis and prognosis, and development of personalized neoantigen mRNA vaccines. Ultimately, this review aims to support clinicians in understanding the current landscape and anticipated innovations in melanoma management to improve clinical decision-making. Full article

(This article belongs to the Special Issue Novel Developments on Skin Cancer Diagnostics and Treatment)

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28 pages, 6896 KB

Open AccessArticle

Regulation of PD-L1 Expression by SAHA-Mediated Histone Deacetylase Inhibition in Lung Cancer Cells

by Umamaheswari Natarajan and Appu Rathinavelu

Cancers 2025, 17(17), 2919; https://doi.org/10.3390/cancers17172919 - 5 Sep 2025

Viewed by 702

Abstract

Background/Objectives: The effects of PD-L1 are mediated via its binding to the PD-1 receptor, which mediates the signals intracellularly to suppress T-cell responses. The expression levels of PD-L1 on cancer cells are an important indicator of immunosuppression and cause poor prognosis in several [...] Read more.

Background/Objectives: The effects of PD-L1 are mediated via its binding to the PD-1 receptor, which mediates the signals intracellularly to suppress T-cell responses. The expression levels of PD-L1 on cancer cells are an important indicator of immunosuppression and cause poor prognosis in several types of cancers. Therefore, the identification and characterization of mechanisms that regulate the expression of PD-L1 in cancer patients is very critical. Method: Our experiment was designed to determine the impact of histone deacetylase (HDAC) inhibitor on PD-L1 expression to reverse tumor-induced immunosuppression using H460 and HCC827 lung cancer cell lines. These cells were treated with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). PD-L1 expression levels were assessed along with key regulatory proteins, including p53, p21, acetyl-histones, DNMT3B, MGMT, and trimethyl histones. Results: In our experiments, suberoylanilide hydroxamic acid (SAHA) was able to reduce the expression of PD-L1 by 60% in a dose-dependent manner. While the level of PD-L1 was significantly reduced, a concurrent increase in levels of p53, p21, and acetyl histone levels were observed in H460 and HCC827 cells following SAHA treatment. Furthermore, SAHA treatment was able to decrease the levels of DNMT3B, MGMT, and tri-methyl histones. It appears that the decrease in PD-L1 expression observed is solely because of p53 or p21WAF1/CIP1-mediated negative control on the transcription process. Conclusion: Our results suggest that SAHA can be used along with immune checkpoint inhibitors to potentiate the therapeutic outcomes in patients with excessive immunosuppression due to PD-L1 expression. Full article

(This article belongs to the Section Molecular Cancer Biology)

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16 pages, 12567 KB

Open AccessArticle

Efficient Tissue Detection in Whole-Slide Images Using Classical and Hybrid Methods: Benchmark on TCGA Cancer Cohorts

by Bogdan Ceachi, Filip Muresan, Mihai Trascau and Adina Magda Florea

Cancers 2025, 17(17), 2918; https://doi.org/10.3390/cancers17172918 - 5 Sep 2025

Viewed by 571

Abstract

Background: Whole-slide images (WSIs) are crucial in pathology for digitizing tissue slides, enabling pathologists and AI models to analyze cancer patterns at gigapixel scale. However, their large size incorporates artifacts and non-tissue regions that slow AI processing, consume resources, and introduce errors [...] Read more.

Background: Whole-slide images (WSIs) are crucial in pathology for digitizing tissue slides, enabling pathologists and AI models to analyze cancer patterns at gigapixel scale. However, their large size incorporates artifacts and non-tissue regions that slow AI processing, consume resources, and introduce errors like false positives. Tissue detection serves as the essential first step in WSI pipelines to focus on relevant areas, but deep learning detection methods require extensive manual annotations. Methods: This study benchmarks four thumbnail-level tissue detection methods—Otsu’s thresholding, K-Means clustering, our novel annotation-free Double-Pass hybrid, and GrandQC’s UNet++ on 3322 TCGA WSIs from nine cancer cohorts, evaluating accuracy, speed, and efficiency. Results: Double-Pass achieved an mIoU of 0.826—very close to the deep learning GrandQC model’s 0.871—while processing slides on a CPU in just 0.203 s per slide, markedly faster than GrandQC’s 2.431 s per slide on the same hardware. As an annotation-free, CPU-optimized method, it therefore enables efficient, scalable thumbnail-level tissue detection on standard workstations. Conclusions: The scalable, annotation-free Double-Pass pipeline reduces computational bottlenecks and facilitates high-throughput WSI preprocessing, enabling faster and more cost-effective integration of AI into clinical pathology and research workflows. Comparing Double-Pass against established methods, this benchmark demonstrates its novelty as a fast, robust and annotation-free alternative to supervised methods. Full article

(This article belongs to the Collection Artificial Intelligence and Machine Learning in Cancer Research)

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33 pages, 2433 KB

Open AccessReview

Expanding Immunotherapy Beyond CAR T Cells: Engineering Diverse Immune Cells to Target Solid Tumors

by Tereza Andreou, Constantina Neophytou, Fotios Mpekris and Triantafyllos Stylianopoulos

Cancers 2025, 17(17), 2917; https://doi.org/10.3390/cancers17172917 - 5 Sep 2025

Viewed by 961

Abstract

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of certain hematologic malignancies, yet its success in solid tumors has been limited by antigen heterogeneity, an immunosuppressive tumor microenvironment, and barriers to cell trafficking and persistence. To expand the reach of [...] Read more.

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of certain hematologic malignancies, yet its success in solid tumors has been limited by antigen heterogeneity, an immunosuppressive tumor microenvironment, and barriers to cell trafficking and persistence. To expand the reach of cellular immunotherapy, multiple immune cell types—γδ T cells, invariant NKT cells, virus-specific T cells, natural killer (ΝΚ) cells, and myeloid effectors such as macrophages and dendritic cells—are now being explored as alternative or complementary CAR platforms. Each lineage brings unique advantages, such as the innate cytotoxicity and safety profile of CAR NK cells, the tissue infiltration and microenvironment-modulating capacity of CAR macrophages, or the MHC-independent recognition offered by γδ T cells. Recent advances in pharmacological strategies, synthetic biology, and artificial intelligence provide additional opportunities to overcome barriers and optimize CAR design and manufacturing scale-up. Here, we review the state of the art in engineering diverse immune cells for solid tumor therapy, highlight safety considerations across autologous, allogeneic, and in vivo CAR cell therapy approaches, and provide our perspective on which platforms might best address current unmet clinical needs. Collectively, these developments lay the foundation for next-generation strategies to achieve durable immunotherapy responses in solid tumors. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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13 pages, 1326 KB

Open AccessArticle

A Comparative Study of Quality of Life and Oncologic Outcomes in Premenopausal Women with Hormone Receptor-Positive Breast Cancer: Bilateral Oophorectomy vs. Gonadotropin-Releasing Hormone Agonist Therapy

by Evrim Erdemoglu, Kathryn J. Ruddy, Matthew R. Buras, Jaxon Quillen, Fergus J. Couch, Janet E. Olson, Laura M. Bozzuto, Nicole L. Larson, Johnny Yi and Kristina A. Butler

Cancers 2025, 17(17), 2916; https://doi.org/10.3390/cancers17172916 - 5 Sep 2025

Viewed by 578

Abstract

Background/Objectives: This study aims to evaluate the quality of life (QoL) and oncological outcomes in premenopausal women diagnosed with hormone receptor-positive breast cancer who are receiving either bilateral oophorectomy (BO) or gonadotropin-releasing hormone agonist (GnRH) therapy. Both methods serve to inhibit ovarian function, [...] Read more.

Background/Objectives: This study aims to evaluate the quality of life (QoL) and oncological outcomes in premenopausal women diagnosed with hormone receptor-positive breast cancer who are receiving either bilateral oophorectomy (BO) or gonadotropin-releasing hormone agonist (GnRH) therapy. Both methods serve to inhibit ovarian function, which is essential for the management of estrogen-dependent tumors; however, their effects on QoL have yet to be fully clarified. Methods: Data were analyzed from the Mayo Clinic Breast Disease Registry, focusing on women under 55 diagnosed with estrogen receptor-positive breast cancer who received either BO or GnRH within one year of diagnosis. QoL was assessed using the Patient-Reported Outcomes Measurement Information System Global-10 (PROMIS-10) at baseline and annually for five years. Results: A total of 181 patients were enrolled in the study; 40 into the BO group and 141 to the GnRH group. Both groups exhibited similar levels of sexual dysfunction after a one-year period; however, the BO group stated a higher frequency of hot flashes. PROMIS-10 scores improved in both mental and physical health over time, with no significant differences between the groups. Within the BO group, one recurrence was observed, in contrast to the GnRH group, which had six events. Nonetheless, the difference in recurrence rates did not reach statistical significance. Conclusions: The long-term QoL and oncologic outcomes for premenopausal women with hormone receptor-positive breast cancer were similar for BO and GnRH therapy. These findings emphasize the need for individualized treatment decisions, considering patient preferences and side effects. Full article

(This article belongs to the Special Issue Long-Term Cancer Survivors: Rehabilitation and Quality of Life)

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14 pages, 1915 KB

Open AccessArticle

Distinct Gut Microbiota Profiles Associated with Advanced Hepatocellular Carcinoma in a Thai Cohort: A 16S rRNA Sequencing Study

by Thanakorn Charoenthanadhol, Jutarop Phetcharaburanin, Theerayut Bubpamala, Aumkhae Sookprasert, Jarin Chindaprasirt, Thanachai Sanlung, Piyakarn Watcharenwong, Siraphong Putraveephong and Kosin Wirasorn

Cancers 2025, 17(17), 2915; https://doi.org/10.3390/cancers17172915 - 5 Sep 2025

Viewed by 615

Abstract

Background: Hepatocellular carcinoma (HCC) remains a major contributor to global cancer mortality. Increasing evidence suggests that the gut microbiota is a key modulator of liver disease progression and a promising source of non-invasive biomarkers. However, regional disparities in microbial profiles, influenced by [...] Read more.

Background: Hepatocellular carcinoma (HCC) remains a major contributor to global cancer mortality. Increasing evidence suggests that the gut microbiota is a key modulator of liver disease progression and a promising source of non-invasive biomarkers. However, regional disparities in microbial profiles, influenced by ethnicity, diet, and environment, limit the generalizability of the existing data. This study aimed to characterize gut microbiota alterations in Thai patients with advanced untreated HCC compared to healthy individuals. Method: Fecal samples from 27 untreated Thai advanced HCC patients were collected, and data from 31 healthy individuals retrieved from a previous study were employed. Gut microbiota profiles were analyzed using 16S rRNA gene sequencing. Results: Alpha diversity was significantly reduced in HCC patients (p < 0.001). At the phylum level, Proteobacteria and Firmicutes were enriched in HCC, whereas Actinobacteria were more abundant in controls. Proteobacteria and Bacteroidota levels were positively correlated with serum alpha-fetoprotein (AFP) levels, whereas Firmicutes were negatively correlated with ALBI scores. Conclusions: Thai patients with advanced HCC exhibited distinct gut microbial signatures, characterized by dysbiosis and expansion of Proteobacteria. These findings support the role of the gut microbiota as a potential non-invasive biomarker for disease severity and prognosis in HCC, underscoring the importance of population-specific microbial studies. Full article

(This article belongs to the Section Molecular Cancer Biology)

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13 pages, 1479 KB

Open AccessArticle

Intensive Treatment in Adult Burkitt Lymphoma with Lymphome Malin B (LMB) Regimen: Excellent Outcomes Despite Substantial Toxicity and Supportive Care Demands

by Ivan Dlouhy, Diana Viegas, Inês Coelho, Alina Ionita, Susana Carvalho, José Cabeçadas and Maria Gomes da Silva

Cancers 2025, 17(17), 2914; https://doi.org/10.3390/cancers17172914 - 5 Sep 2025

Viewed by 568

Abstract

Background: Burkitt lymphoma is a rare, aggressive B-cell neoplasm with frequent central nervous system (CNS) involvement, treated with intensive multidrug regimens associated with rituximab. The aim of this study was to assess the efficacy, safety, and feasibility of the LMB protocol in [...] Read more.

Background: Burkitt lymphoma is a rare, aggressive B-cell neoplasm with frequent central nervous system (CNS) involvement, treated with intensive multidrug regimens associated with rituximab. The aim of this study was to assess the efficacy, safety, and feasibility of the LMB protocol in adults with BL in a real-world setting. Methods: We included 55 patients with BL diagnosis according to the 2008 WHO classification, treated with LMB protocol associated with rituximab. Low-risk patients (no bone marrow or CNS involvement) were treated in the group B arm, while high-risk patients were placed in group C, which was further stratified by age and CNS infiltration. Results: Thirty-four patients (62%) were treated in group B and 21 patients (38%) were treated in group C, with a median age of 34 years (16–77). Extranodal infiltration was present in 71% patients, including 11 (20%) with CNS involvement. After a median follow up time of 7 years, the complete remission rate was 85%, and progression-free and overall survival at 3 years were 79% and 84%, respectively. Patients with CNS infiltration had an inferior survival rate (55% at 3 years). Grade 3–4 toxicities were frequent, mainly hematologic, infectious, and mucosal. Treatment required substantial supportive care, including 1604 transfusions and 4696 days of hospitalization. Patients over 60 years had poorer outcomes and higher toxicity. Conclusions: The LMB protocol demonstrated high survival rates in adult BL, although at the cost of significant toxicity and considerable health care resource utilization. Outcomes remained suboptimal in patients with CNS involvement despite treatment intensification. Full article

(This article belongs to the Special Issue Burkitt Lymphoma: From Pathogenesis to Current Treatments)

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15 pages, 2620 KB

Open AccessArticle

Calcium and Albumin Blood Tests, Ethnicity, and Cancer Incidence in Primary Care in the UK

by Liz Down, Melissa Barlow, Luke T. A. Mounce, Jessica Watson, Samuel W. D. Merriel, Sarah E. R. Bailey and Tanimola Martins

Cancers 2025, 17(17), 2913; https://doi.org/10.3390/cancers17172913 - 5 Sep 2025

Viewed by 585

Abstract

Objectives: This study aimed to assess any ethnic differences in blood calcium and albumin levels for patients receiving these tests in primary care, and to investigate how this affects the use of these markers in assessing cancer risk. Methods: The analysis was based [...] Read more.

Objectives: This study aimed to assess any ethnic differences in blood calcium and albumin levels for patients receiving these tests in primary care, and to investigate how this affects the use of these markers in assessing cancer risk. Methods: The analysis was based on a primary care dataset comprising patients in England. Multilevel logistic regression was used to investigate the relationship between blood test results and cancer risk by ethnic group. Results: A total of 4,632,856 patients were eligible for the albumin analysis, and 1,979,763 for the calcium analysis. Raised calcium levels were indicative of an increased risk of cancer, with diagnostic odds ratios (ORs) ranging from 2.0 to 2.7 for the different ethnic groups. ORs for myeloma were between 6.6 and 13.6. Similarly, low albumin was associated with an increased risk of cancer with an OR of between 3.2 and 3.8, myeloma (OR between 8.7 and 10.0), and liver cancer (OR between 9.2 and 15.7). Conclusions: Albumin and corrected calcium were effective indicators of cancer risk, and more specifically of risk of myeloma. Albumin levels were also linked with liver cancer risk. While there are some differences in typical corrected calcium and albumin levels between ethnic groups, there was no evidence that this had an effect on the usefulness of these markers to infer cancer risk. Full article

(This article belongs to the Section Cancer Causes, Screening and Diagnosis)

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13 pages, 663 KB

Open AccessArticle

Radiomics Combined with Transcriptomics Improves Prediction of Breast Cancer Recurrence, Molecular Subtype and Grade

by George K. Acquaah-Mensah, Boris Aguilar and Kawther Abdilleh

Cancers 2025, 17(17), 2912; https://doi.org/10.3390/cancers17172912 - 5 Sep 2025

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Abstract

Background/Objectives: Breast cancer (BrCA) is among the deadliest cancers for women in the world. The disease has four distinct molecular subtypes which can be determined by gene expression profiling. Understanding these subtypes has enabled the development of targeted therapeutics. Additionally, following initial successful [...] Read more.

Background/Objectives: Breast cancer (BrCA) is among the deadliest cancers for women in the world. The disease has four distinct molecular subtypes which can be determined by gene expression profiling. Understanding these subtypes has enabled the development of targeted therapeutics. Additionally, following initial successful treatment, some patients experience disease recurrence events. Methods: In this study, we used radiomics coupled with machine learning techniques to predict molecular subtypes and disease recurrence events from a dataset of MRI features deriving from a single-institutional, retrospective collection of 922 biopsy-confirmed invasive BrCA patients. The feature-rich and comprehensive dataset consists of radiomic as well as demographic, clinical, and molecular subtype information. We focused our analyses on Black and White patients who were 50 years or younger at diagnosis (n = 346) to identify racial disparities that exist between molecular subtypes and disease recurrence events. Random Forest and AdaBoostM1 were applied to over 500 radiomics features. Results: Radiomics alone or combined with gene expression data can accurately predict molecular subtype and disease recurrence events for both racial groups. In total, we found over 40 radiomics features that have significant associations with race. The radiomic features that are most predictive in the Breast and Fibroglandular Tissue Volume imaging category for Black patients was breast volume (Breast_Vol) and for White patients was post contrast tissue volume (TissueVol_PostCon). Conclusions: These results suggest that radiomics can be used to predict differences in BrCA recurrence and molecular subtype between racial groups and can have an impact on clinical outcomes. Full article

(This article belongs to the Section Molecular Cancer Biology)

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28 pages, 15046 KB

Open AccessArticle

Application of Single-Cell Sequencing and Machine Learning in Prognosis and Immune Profiling of Lung Adenocarcinoma: Exploring Disease Mechanisms and Treatment Strategies Based on Circadian Rhythm Gene Signatures

by Qiuqiao Mu, Han Zhang, Kai Wang, Lin Tan, Xin Li and Daqiang Sun

Cancers 2025, 17(17), 2911; https://doi.org/10.3390/cancers17172911 - 5 Sep 2025

Viewed by 777

Abstract

Background: The circadian rhythm regulates important functions in the body, such as metabolism, the cell cycle, DNA repair, and immune balance. Disruption of this rhythm can contribute to the development of cancer. Circadian rhythm genes (CRGs) are attracting attention for their connection [...] Read more.

Background: The circadian rhythm regulates important functions in the body, such as metabolism, the cell cycle, DNA repair, and immune balance. Disruption of this rhythm can contribute to the development of cancer. Circadian rhythm genes (CRGs) are attracting attention for their connection to various cancers. However, their roles in LUAD are not yet well understood. Additionally, our knowledge of how they function at both the bulk tissue and single-cell levels is limited. This gap hinders a complete understanding of how CRGs impact the development and outcomes of LUAD. Methods: We selected 554 CRGs from public databases. We then obtained transcriptome data from TCGA and GEO. A total of 101 machine learning algorithm combinations were tested using 10 algorithms and 10-fold cross-validation. The best-performing model was based on Stepwise Cox regression and SuperPC. This model was validated with additional datasets. We also examined the relationships between CRGs, immune features, tumor mutation burden (TMB), and the response to immunotherapy. Drug sensitivity was also assessed. Single-cell data identified the cell types with active CRGs. Next, we performed qRT-PCR and other basic experiments to validate the expression of ARNTL2 in LUAD tissues and cell lines. The results indicated that ARNTL2 may play a key role in lung adenocarcinoma. Results: The CRG-based model clearly distinguished LUAD patients based on their risk. High-risk patients exhibited low immune activity, high TMB, and poor predicted responses to immunotherapy. Single-cell data revealed strong CRG signals in epithelial and fibroblast cells. These cell groups also displayed different communication patterns. Laboratory experiments showed that ARNTL2 was highly expressed in LUAD. It promoted cell growth, movement, and invasion. This suggests that ARNTL2 may play a role in promoting cancer. Conclusions: This study developed a machine learning model based on CRGs. It can predict survival and immune status in LUAD patients. The research also identified ARNTL2 as a key gene that may contribute to cancer progression. These findings highlight the significance of the circadian rhythm in LUAD and provide new perspectives for diagnosis and treatment. Full article

(This article belongs to the Special Issue Advances in Cell and Gene Therapy in Tumors: From Bench to Bedside)

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Cancers, Volume 17, Issue 17 (September-1 2025) – 220 articles

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