Onco: Covering the Field of Cancer Research and Cancer Therapies in 2024

1. Introduction

The year of 2024 was successful regarding the scientific performance of Onco. This is justified by the high scientific quality of the papers published in this journal, which covered a significant range of contemporary areas of preclinical, translational, and clinical research in the field of oncology. In particular, the studies published in Onco last year addressed and provided new insights into fundamental topics of cancer research and therapy, including (i) the mechanisms of resistance to various treatments; (ii) biomarkers for prognosis and prediction; (iii) immune checkpoints and their ligands for prognosis and treatment; (iv) therapeutic drugs, therapeutic strategies, and treatment options; (v) cellular immunotherapy and cancer vaccines; (vi) the regulation of apoptotic cell death; and (vii) imaging technologies for cancer detection, including biology systems and machine learning (ML) for the design of anticancer therapeutic modalities. Below, we discuss the insights into the various scientific topics in cancer research and therapy reported in these publications.

2. Mechanisms of Resistance to Various Treatments

Malhotra P. and Rahman R. [1] provided a comprehensive review of the interactions between intratumor heterogeneity and residual infiltrative disease in isocitrate dehydrogenase wild-type glioblastoma multiforme (GBM), which is an aggressive cancer type resistant to multimodal treatments. Its resistance is caused by residual tumor cells located at the infiltrative margin after treatment, which give rise to recurrent GBM tumors. The authors explain that tumor cells at the infiltrative margin have high heterogeneity and are likely to be resistant to chemo-radiotherapy as they are located in regions of the brain that are difficult to access. In conclusion, there is an imperative need to apply next-generation therapeutic approaches that can restrict intratumoral heterogeneity by efficiently eliminating clinically important tumor subclones. Yeh C. et al. [2] proposed the development of personalized diagnostic technologies for drug response prediction that are simple, affordable, and provide fast results with high sensitivity and accuracy for cancer patients who did not respond to or developed resistance to targeted therapies and immune checkpoint blockades. In this respect, the authors developed a novel technology based on the isolation of cell-free mRNA from a single patient to predict the drug types that will induce clinical benefits for this patient. Thus, they proposed the development of personalized predictive methodologies for clinical responses to therapeutic drugs based on a patient’s gene signature expression levels (called patient-derived gene expression-informed anticancer drug efficacy (PGA)), which is quite essential for advancing the field of precision oncology. The gene signature was utilized to rank the effectiveness of over 700 anticancer drugs from a library, aiming to identify the most suitable treatment(s) for each patient. Notably, PGA was also prospectively tested using gene expression levels and genetic alterations from a real-world cohort of patients with non-small cell lung cancer to pinpoint possibly effective drugs.

Perrone M. et al. [3] were the first to investigate the impact of the JAK2 V6117F somatic mutation, which is associated with the germline GGCC_46/1 haplotype, in resistance to therapies in patients with myeloproliferative neoplasms (MPNs). The authors found no correlation between drug-related resistance and the C/G allele, whereas patients carrying the G/G allele tended to exhibit MPN progression to myelofibrosis accompanied by clinical parameters favoring therapy resistance. The authors concluded that in-depth knowledge of the GGCC haplotype’s implications can play a pivotal role in refining therapeutic strategies, enabling the development of more personalized therapies that maximize effectiveness and minimize potential adverse events.

3. Biomarkers for Prognosis and Prediction

Roy A.M. et al. [4] used large databases to perform a meta-analysis for the identification of biomarkers that could predict clinical responses to neoadjuvant chemoimmunotherapy in patients with triple-negative breast cancer (TNBC). Complete pathologic responses were significantly increased among patients with positive lymph nodes and an Eastern Cooperative Oncology Group performance score of 0, receiving neoadjuvant chemotherapy along with checkpoint inhibitors. Interestingly, patients positive for programmed death ligand 1 (PD-L1) did not experience any clinical benefit from this combined treatment compared to PD-L1-negative patients. The authors suggested that identifying additional predictive biomarkers for clinical responses to combined neoadjuvant chemoimmunotherapy will be beneficial for selecting patients with TNBC who are most likely to respond to this regimen.

Gili R. et al. [5] reported that in head and neck cancers, proper clinical follow-up protocols aiming to detect recurrences relatively shortly (up to 2 years) after the first treatment are lacking, resulting in local and distant relapses. Radiological follow-up is the most common method applied to identify locoregional and distant recurrences, but there is no clear benefit to patients’ overall survival. Therefore, circulating biomarkers are additionally needed to predict disease recurrence. The authors discussed the essential role of pre-treatment low-circulating Epstein–Barr Virus (EBV) DNA levels in nasopharyngeal carcinoma, which are associated with early-stage disease and better prognosis [6,7], whereas in Human Papillomavirus (HPV)-positive oropharyngeal carcinomas, a decrease in circulating HPV-DNA post treatment is associated with a favorable prognosis [8]. Considering that most recurrences in head and neck cancers are locoregional and only a small percentage of them (10–20%) are asymptomatic, radiological follow-up in conjunction with patients’ symptomatology, along with the quantitation of circulating viral DNA (in cases of EBV- and HPV-related cancers), should be considered as the preferable monitoring strategy.

Ferreira A.F. et al. [9] discussed the impact of the Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) as predictive markers for the survival of elderly patients with cancer. To this end, they performed an in-depth analysis of the results from 38 relative studies that were mostly conducted in Asia, particularly in Japan, China, and the Republic of Korea. Although there was a tendency for poor overall survival in patients with gastric cancer and a low PNI, most of these studies did not establish a significant relationship between the PNI and survival metrics, such as cancer-specific survival, progression-free survival, disease-free survival, recurrence-free survival, and mortality. The results regarding the prognostic significance of CONUT in predicting survival were mixed and inconclusive. Given the low number of studies analyzed, the authors proposed the need to include data from more studies conducted in other regions, including North America and Europe, where elderly patients with cancer comprise a significant part of the population.

The overexpression of tumor-associated antigens (TAAs) may have a prognostic role in monitoring clinical outcomes to therapeutic regimens; however, their utilization as biomarkers for the early detection of malignancies remains controversial. In their review, Mohamed E. et al. [10] discussed the capacity of TAAs to function as early detection markers for lung cancer (LC). Given their low sensitivity and specificity, TAAs are not suitable for early diagnosis, and therefore, it is important to detect circulating protein signatures specific for LC. Detecting such non-invasive biomarkers will enable early diagnosis and identify novel therapeutic targets for LC.

In their case report, Karbhari N. and Khagi S. [11] explored the potential therapeutic benefits of marine-derived compounds (namely SeaCare^®) in the treatment of glioblastoma. Glioblastoma typically leads to inevitable recurrence and progression, making it one of the most fatal and difficult cancers to manage. The authors present two cases where the use of marine-derived products, including those found in nutraceutical products, demonstrated promising effects in managing the disease. The report suggests that the mechanisms underlying the therapeutic effects of marine-derived compounds are multifaceted. One of the key processes appears to be modifying the tumor immune microenvironment. Specifically, the changes observed in tumor-associated macrophages (TAMs) within the tumor microenvironment played a central role in the observed clinical improvements. TAMs, which are crucial in regulating immune responses within tumors, are thought to contribute to tumor progression when they acquire a pro-tumorigenic phenotype. Marine-derived compounds seem to modify the activity of these macrophages, thereby suppressing their tumorigenic effects and potentially enhancing the immune response against the tumor. These findings suggest that marine products may offer a novel therapeutic approach for glioblastoma, which warrants further investigation to better understand their full potential and the mechanisms at play. Given the lack of effective treatment options for glioblastoma, these compounds represent an exciting area of research that can lead to new, more effective strategies to manage this deadly disease.

4. Immune Checkpoint Inhibitors for Prognosis and Treatment

Three prime repair exonuclease 1 (TREX1) is an enzyme that blocks cGAS–STING-induced activation of type I interferons via the degradation of cytosolic double-stranded DNA, dampening antitumor immunity. The down-regulation of TREX1 function, either through gene deletion or therapeutic targeting, protected experimental animals from the growth of transplantable tumors and increased T cell infiltration into the tumor [12,13,14]. In their review article, Hawillo K. et al. [15] discussed novel mechanistic pathways aiming to promote antitumor immune reactivity via combinatorial treatments in pre-clinical therapeutic cancer models, including the blockade of TREX1 and immune checkpoint inhibition. Such therapeutic combinations pave the way for the discovery of efficient TREX1 inhibitors, which will designate novel anticancer drugs to be tested in phase I clinical trials as single agents and in combination with immune checkpoint inhibitors.

The role of PD-L1 expression in oral squamous cell carcinoma (OSCC) for predicting clinical outcomes based on the application of immune checkpoint blockades (PD-1 and PD-L1) is not yet fully understood. Many clinical studies face challenges due to heterogeneous patient cohorts and the use of varying immunohistochemical methods for the quantitation of PD-L1 expression in the tumor microenvironment. In their study, Leporace-Jiménez F. et al. [16] presented the results of a monocentric clinical trial involving patients with OSCC, in whom the expression levels of PD-L1 were classified as low with a Combined Positive Score (CPS) ranging from 1 to 20 or as high with a CPS of ≥20. PD-L1 expression was examined along with clinicopathological characteristics, including the tumor size, stage, lymph node involvement, and clinical outcomes based on overall survival. PD-L1 positivity was more intense in advanced vs. early-stage tumors and in T4 vs. T1 tumors. Moreover, all lymph node metastases were PD-L1+, with 60% associated with patients who initially had high PD-L1 expression. Overall survival in a follow-up period of 2–34.5 months did not correlate with the levels of PD-L1 expression. Given the controversy regarding the correlation between PD-L1 expression and favorable or unfavorable prognosis in head and neck squamous cell carcinomas, the authors suggested the need for a consensus on a method to accurately quantify PD-L1’s levels of expression to reliably correlate PD-L1 positivity with survival. Furthermore, they proposed conducting additional research to examine PD-L1 expression in patients with OSCC and to evaluate its significance as a prognostic biomarker.

Gama J.M. et al. [17] reviewed the role of lymphocyte-activation gene 3 (LAG-3) and the T cell immunoglobulin and ITIM domain (TIGIT) as new promising immune checkpoints that can be therapeutically targeted alone or in combination with the well-established PD-1/PD-L1 axis. The authors comprehensively described the mechanisms underlying the interactions of LAG-3 with major histocompatibility class II molecules expressed on CD4+ T cells, resulting in the inactivation of their functional programs. They discussed various approaches that were developed for LAG-3-targeted therapy, including the use of LAG-3 agonists and combination treatments with anti-PD-1 antibodies. The expression profile of TIGIT in natural killer (NK) cells, regulatory T cells (Tregs), cytotoxic T cells, and dendritic cells is also discussed in the context of functional alterations in these cell types, which are reversible upon the therapeutic targeting of TIGIT. They discussed ample examples of the synergistic effect of LAG-3 or TIGIT inhibition with PD-1/PD-L1 blockades or other therapeutic regimens, including radiotherapy, all of which pave the way for a significant enhancement in the antitumor reactivity mediated by CD8+ T cells.

5. Therapeutic Drugs, Therapeutic Strategies, and Treatment Options

Cannabinoids may have dual roles in cancer therapy: they exhibit cytotoxic effects on cancer cells but also help alleviate the common side effects associated with chemotherapy. Nahler G. [18] comprehensively reviewed experimentations in animal tumor models, testing the clinical efficacy and side effects of cannabinoids combined with standard chemotherapeutics. The results from these preclinical studies show that there was increased antitumor activity when therapeutic regimens based on platinum compounds, doxorubicin, paclitaxel, docetaxel, tamoxifen, and aromatase inhibitors were combined with cannabinoids. Such enhanced antitumor activity mainly occurred due to the ability of cannabinoids to suppress multiple resistance mechanisms induced by tumor cells during treatments. In addition, there is increasing evidence of clinical benefits with combining cannabinoids with gemcitabine in patients with pancreatic cancer or with temozolomide in patients with glioblastoma [19,20,21,22]. Cannabinoids offer an additional advantage by potentially mitigating the side effects associated with cancer treatments, often with fewer adverse events compared to other supportive care medications. The ability of cannabinoids to reduce nausea and vomiting and stimulate appetite has also been well documented. Moreover, studies indicate that cannabinoids may help manage neuropathic pain, anxiety, and oral mucositis, while also potentially decreasing the organ toxicity of chemotherapy. The author concluded that the paucity of preclinical data on the beneficial role of cannabinoids in cancer therapy, along with the few clinical studies on patients with pancreatic cancer and glioblastoma, has opened new avenues for testing and optimizing their efficacy in larger patient cohorts.

In their review article, Guernsey-Biddle C. et al. [23] discussed that current epidermal growth factor receptor (EGFR)-targeting therapies for metastatic colorectal cancer using the monoclonal antibodies cetuximab and panitumumab are effective only in a minority of patients, mostly due to primary and acquired immune resistance that develops during treatment. By underlying the need to overcome immune resistance through targeting molecular components involved in the EGFR signaling pathway, they propose the EGFR ligands epiregulin (EREG) and amphiregulin (AREG) as the most suitable candidates to target with monoclonal antibodies, either naked or conjugated with drugs (antibody–drug conjugates). They discussed that EREG and AREG are overexpressed in colorectal cancer and therefore have a central role in acquiring clinical benefits from EGFR-targeted therapies as well as in the development of therapy resistance. The review comprehensively examined the precise EREG- and AREG-induced mechanisms underlying resistance to EGFR-targeted therapy. It is mandatory to reverse resistance via effectively targeting the key components controlling these mechanisms.

Clinical outcomes in patients with unresectable pancreatic neuroendocrine neoplasms (panNEN) can be improved with the use of metformin, an antidiabetic drug. Metformin has also been shown to exert antitumor effects in experimental tumor models [24]. In their research article, Maruzen S. et al. [25] demonstrated that metformin exerts its tumor cytostatic effects in human panNEN cells by suppressing mitochondrial respiration and AMP-activated protein kinase (AMPK) activation. These findings provide the first evidence of the direct antitumor activity of metformin in panNEN.

Barry S.L. et al. [26] reported a crucial case that highlights the complexities of managing anaplastic thyroid cancer (ATC) even with the promising advances in BRAF/MEK-targeted therapies. While the patient in the described case experienced a rapid and effective clinical response, the report underscored the potential for severe complications, illustrating that despite initial positive outcomes, treatment regimens for ATC can be fraught with challenges. The authors emphasized that although BRAF/MEK-targeted therapies have significantly advanced the molecular understanding and treatment of ATC, there remain instances where these therapies either induce resistance or fail to provide a sufficient response. This raises a critical issue in the management of ATC, particularly when patients may develop resistance to BRAF/MEK inhibitors or are non-responsive to these treatments altogether. To address these limitations, Barry et al. call for continued research into additional treatment strategies that can offer benefits for those with BRAF/MEK-resistant or non-responsive ATC. Conducting ongoing research is essential to ensure that all individuals diagnosed with this aggressive form of thyroid cancer can benefit from the therapeutic potential of targeted therapies and that healthcare providers are adequately equipped to manage both the efficacy and possible complications of these treatments.

In their review article, Temperley H.C. et al. [27] explored the promising potential of transarterial chemoembolization (TACE) as a treatment option for patients with locally advanced rectal cancer (LARC). TACE is an innovative therapeutic approach that allows for the targeted delivery of chemotherapy directly into the tumor mass, which can minimize systemic side effects compared to traditional chemotherapy. The authors highlighted that current studies on TACE in patients with LARC have shown encouraging results regarding clinical efficacy. The key outcomes that were evaluated include tumor load reduction, the control of metastases, and improvement in overall survival. Notably, TACE has been demonstrated as both a safe and promising therapeutic regimen for managing LARC, with manageable side effects that do not outweigh its benefits. However, the authors stress the importance of large-scale clinical trials for further validation. Larger, more comprehensive studies are necessary to establish the full potential of TACE in LARC treatment, better understand its long-term effects, and refine treatment protocols. Continuing this research can pave the way for TACE to become a standard constituent of the therapeutic arsenal for patients with LARC, improving outcomes and quality of life.

Lantwin P. et al. [28] investigated the role of DNA damage repair (DDR) gene deficiency in prostate cancer (PC) progression, particularly in the occurrence of early metastases. To this aim, they tested the effect of knocking down DDR and checkpoint proteins, including BRCA2 and ATM, on the migratory behavior and oxidative stress in PC cell lines. The knockdown of BRCA2 or ATM significantly increased the migratory activity, with a concurrent increase in oxidative stress being identified by higher levels of reactive oxygen species (ROS). Interestingly, ROS inhibition blocked the enhanced motility of BRAC2- or ATM-deficient PC cells. These data improve our understanding of the factors that cause an increased risk of metastatic dissemination in patients with PC and can help in the development of novel therapeutic interventions aimed at blocking pathways leading to increased levels of oxidative stress.

The role of brain pericytes in the tumor microenvironment of brain tumors has been relatively underexplored. Brain cancers, which have poor prognoses and markedly affect patients and their families, are known to recruit local non-transformed cells to support tumor growth. Pericytes, which are specialized cells that surround the blood vessels in the brain, are of particular interest due to their localization and supportive functions in the vascular system. McCullough S. et al. [29] identified several brain cancer-secreted factors that can influence brain pericyte activity. These factors appear to alter key pericyte functions, such as their role in maintaining the integrity of the blood–brain barrier, regulating blood flow, and influencing immune responses within the tumor microenvironment. The researchers found that brain tumors may exploit these mechanisms to promote tumor progression and metastasis by modifying the activity of pericytes. The research provides valuable insights into how brain tumors manipulate pericyte functions to create a supportive microenvironment that aids tumor growth and survival. The findings from this study provide a deeper understanding of the molecular interactions between brain tumors and the cells within their immediate environment. By uncovering these mechanisms, McCullough et al. paved the way for potential therapeutic strategies that target pericyte–tumor interactions, offering new avenues for treating brain cancers more successfully.

In their review, Jagtiani P. et al. [30] assessed the existing meta-analyses from four clinical studies to evaluate the impact of the extent of resection—specifically subtotal resection (STR) versus gross total resection (GTR)—on the overall survival in patients with GBM, the most common malignant brain tumor in adults. A quality assessment of all four studies was highly rated, and a pooled analysis of these studies revealed a significant survival advantage for patients undergoing GTR compared to those who underwent STR. Despite this finding, the evidence was graded as Class III according to standard classification criteria, indicating weak credibility. This suggests that while GTR may offer a slight survival benefit over STR, the quality of evidence supporting this conclusion is not robust enough to definitively guide clinical practice. The authors emphasized that further research is needed to strengthen the evidence-based results regarding the optimal extent of resection in patients with GBM. Given the lack of a clear consensus on this issue, additional studies are crucial to refine surgical strategies and improve patient outcomes.

By using systems biology to study protein–protein interactions involved in aberrant signaling pathways in chronic lymphocytic leukemia, Pozzati G. et al. [31] identified protein networks that can be used as a platform for designing novel multi-targeted inhibitory therapeutic modalities to generate more efficient clinical responses as opposed to single-target inhibition. They also succeeded in developing a rank order of the identified proteins in terms of their therapeutic potential. The results from such a theoretical systems biology model need to be validated in knockdown experimentations with small molecule inhibitors and/or siRNAs.

Catecholamines, which include hormones like adrenaline and noradrenaline, have been shown to have both positive and negative effects on cancer depending on the context, such as the presence of physical exercise or stress. Weeber P. et al. [32] investigated the complex relationship between catecholamine signaling, stress, exercise, and cancer progression. The authors aimed to explore whether the expression of adrenergic receptor isoforms could explain the contradictory effects of catecholamines. Their findings suggest that the impact of catecholamines on cancer progression and metastasis is influenced by the specific adrenergic receptor isoforms expressed on cancer cells. These receptors are diverse, with nine different adrenergic receptor isoforms identified. Their study provides proof of principle that the differential expression of these isoforms in various cancer types could explain why some cancers respond positively to exercise and stress, while others may aggressively progress under the same conditions. This insight has significant implications for personalized cancer treatment. Since cancers express adrenergic and other receptors differently, understanding these variations could help tailor treatments, including exercise regimens, stress management, and pharmacological interventions, to improve outcomes for individual patients. Ultimately, this research highlights the potential for more targeted therapies based on the unique receptor profile of each patient’s tumor.

In their report, de Castro Coelho E.M. et al. [33] showed that physical exercise has a positive impact on quality of life and self-esteem in women with breast cancer, proposing to communities and healthcare professionals to put forward regular exercise courses for these patients. The authors underlined the need to improve the exercise program in terms of both duration and weekly frequency to achieve further improvements in the physiological health of breast cancer survivors.

6. Cellular Immunotherapy and Cancer Vaccines

Lehmann A.A. et al. [34] introduced the concept of the comprehensive monitoring of CD8+ T cell-mediated antitumor peptide immune responses to obtain insights into the host’s response to cancer rather than focusing solely on specific CD8+ T cell epitopes. Practically, this can be obtained by utilizing multiple peptides with overlapping sequences (i.e., mega-peptide pools) covering a large spectrum of anti-tumor CD8+ T cell responses, ultimately resulting in tumor rejection. However, such a scenario can be too ambitious due to (i) the plethora of tumor-associated peptides expressed in the context of MHC class I and class II molecules in cancer cells; (ii) the levels of self-tolerance for these tumor-associated peptides; (iii) epitope spreading, which increases the magnitude of CD8+ T cell reactivity against multiple tumor peptides; and (iv) the exhaustion of such tumor peptide-specific antitumor immunity upon the continuous interactions between CD8+ T cells with autologous tumor cells. Despite these caveats, the authors concluded that the systematic and comprehensive monitoring of CD8+ T cell responses to tumor-associated peptides with overlapping sequences leads to more solid conclusions concerning an individual’s anticancer immunity as opposed to testing CD8+ T cell responses to a restricted number of tumor epitopes. Such monitoring could result in the identification of immunogenic tumor peptides to be included in multipotent therapeutic cancer vaccines.

In her review article, Bartunkova J. [35] discussed the development and clinical testing of an autologous dendritic cell vaccine (DCVAC) in patients with epithelial ovarian cancer (EOC). The vaccine proved to be safe and showed clinical efficacy by prolonging progression-free survival and overall survival in a phase II trial involving patients with EOC at various stages of the disease. Interestingly, the vaccine proved to be effective in patients whose tumors were infiltrated by low numbers of CD8+ T cells and characterized by a low mutational burden. Pre-existing antitumor immunity was an additional biomarker predicting clinical responses to the DCVAC. The author concluded that the discovery of additional biomarkers that can be incorporated into routine diagnostic evaluations will help inform and optimize treatment selection in the future. Such a therapeutic regimen will be mostly based on a combination of treatment modalities tailored to the unique baseline immune characteristics of the tumor microenvironment, aiming to alter the disease’s evolution.

Cellular immunotherapy for cancer, based on the adoptive transfer of autologous chimeric antigen receptor (CAR)-T cells, is an established treatment regimen for patients with hematological malignancies. In their review, Madrigal J.A. and Crispin J.C. [36] discussed some of the most important aspects that are relevant to the utilization of CAR-T cells with a focus on hematological cancers and beyond, namely their application in patients with autoimmune diseases such as systemic lupus erythematosus, idiopathic inflammatory myositis, and systemic sclerosis. Most interestingly, the authors analyzed a series of factors that regulate the clinical efficacy of CAR-T cells and their application in clinical designs as a second-line treatment. Emphasis was also placed on the arming of CAR-T cells with proinflammatory cytokines to improve their clinical efficacy. Another important issue that was thoroughly discussed is the generation of allogeneic CAR cells (T and NK cells) for circumventing the high cost and time-consuming production of autologous CAR-T cells. The review also discussed significant emerging concerns that require attention, such as the risk of secondary cancers linked to CAR-T cell therapy, possibly caused by the incorporation of viral vectors but also via the emergence of genetic or epigenetic alterations throughout the process of T cell expansion. The review also discussed the association of CAR-T cell therapy with several acute clinical complications, such as the cytokine release syndrome, cytopenias, neurotoxicity, and infections. The authors noted that these potential adverse events must be carefully weighed to avoid life-threatening side effects when applying CAR-T cell therapy.

7. Regulation of Apoptotic Cell Death

In his commentary, Mirzayans R. [37] discussed the process of anastasis, which refers to the ability of tumor cells to functionally recover from advanced stages of apoptosis. This process explains the previously unexpected observation from clinical studies in which poor clinical efficacy was associated with increased levels of apoptosis, contrasting with the hypothesis that tumor cells develop resistance to therapies via their ability to evade drug-induced apoptosis [38,39,40]. The author also discussed alternative mechanisms contributing to tumor cell survival post engagement of apoptosis, which can be attributed to intratumoral heterogeneity, whereby different tumor subclones develop resistance to treatments via distinct mechanistic pathways. The commentary concluded that apoptosis may not be the ultimate goal of anticancer therapies, but in essence, it serves as a critical juncture where proapoptotic therapies can induce adverse side effects. These effects often lead to an initial reduction in tumor size being overshadowed by excessive and subsequent tumor regrowth. This functional role of apoptosis should be acknowledged for its ability to improve the clinical outcomes of personalized anticancer therapies.

The Hippo-YAP/TAZ signaling pathway is responsible for constantly modulating the balance between cellular proliferation and apoptotic pathways, which control the internal environment of organs and tissues. For this reason, genetic alterations in its molecular components may dysregulate certain signaling pathways, resulting in uncontrolled cellular proliferation and tumorigenesis. In their review, Wang Y. and Rui L. [41] discussed the significant impact of the dysregulated Hippo-YAP/TAZ signaling pathway in the pathogenesis and evolution of liver cancer, and by analyzing underlying genetically modified mechanistic pathways, they revealed novel candidate therapeutic targets for this cancer type. Given the lack of YAP-specific blockers, the authors underlined the unmet need for the discovery and validation of YAP-selective inhibitors, which will be crucial for the design of novel treatment protocols. A second issue stressed in this review is that the Hippo-YAP pathway may be interconnected with other oncogenic signaling pathways linked to liver cancer. The exploration of such pathways will further improve our understanding of liver cancer evolution, offering additional innovative means regarding the discovery of novel therapeutic drugs.

8. Imaging Technologies for Cancer Detection and Biology Systems Including Machine Learning for Design of Anticancer Therapeutic Modalities

In their review, Narayanan S. et al. [42] discussed the importance of the involvement of Raman spectroscopy in clinical oncology, particularly precision oncology via advancing the field of individualized care. To this end, the authors reported that the levels of circulating tumor DNA (ctDNA) and therapeutic drug monitoring (TDM) constitute two important strategies to move the field of precision oncology forward. The quantitation of plasma ctDNA has considerable significance in disease recurrences and metastases, whereas TDM assesses plasma drug levels to guide efficient treatment and suggest an appropriate clinical follow-up schedule based on the risk for disease progression. Current methods for characterizing small molecules, including fluorescence-based and chromatographic techniques, can be constrained by high expenses, extended processing times, and large cumbersome equipment. The authors proposed the use of surface-enhanced Raman spectroscopy (SERS) as an easy-to-handle portable device, offering the possibility for a fast, cost-effective evaluation of clinically significant variables at the point of care, along with the swift initiation of necessary treatment adjustments. In particular, the authors first introduced Raman spectroscopy and SERS, followed by an exploration of their applications in clinical oncology, focusing particularly on the use of SERS in TDM and ctDNA quantification.

Zadeh M.Z. [43] discussed novel applications of positron emission tomography (PET) fused with computed tomography for evaluating multiple myeloma, referring to the assessment of bone turnover, early and delayed imaging scans, improved PET radiotracers, and artificial intelligence methodologies. The author extensively addressed the contribution of these innovative applications for the accurate assessment of osteolytic lesions, atherosclerosis, and residual disease in clinical research studies and clinical settings.

Although immune checkpoint blockades (ICBs) have revolutionized the field of cancer therapy, nearly 40% of patients receiving this type of immunotherapy develop resistance and eventually relapse [44]. Comprehensive analyses of the mechanisms of underlying resistance to ICB are crucial for designing more efficient clinical protocols combining ICB with other therapeutic regimens that will circumvent the onset of immune resistance, ultimately resulting in improved clinical responses. To this end, a meta-analysis with a large patient cohort is a cornerstone to obtain a better understanding of how immune resistance to ICB is developed. Mestrallet G. [45] used patient cohorts with various cancer types, including melanoma, clear cell renal carcinoma, glioblastoma, bladder cancer, and stomach cancer, for whom detailed information on immunologic and clinical responses was accessible on the CRI iAtlas website. Four different types of ML approaches were developed to precisely predict the clinical outcomes to ICBs based on immune response profiles, distinguishing between patients developing resistance and disease progression, and clinical responders. Based on these ML approaches, 20 algorithmic models were generated, which succeeded in predicting resistance vs. response to ICB in 79% to 100% of all patients analyzed. Such a multi-ML approach will improve treatment decisions in the frame of precision oncology and the outcomes of patients undergoing treatment with ICBs.

9. Conclusions

The scientific papers published in Onco in 2024 reported advancements in the field of oncotargets and cancer therapies with a focus on identifying biomarkers, molecular targets, drugs, therapeutic regimens, apoptotic cell death, imaging technologies, and clinical trials. These advancements have the potential to significantly contribute to the progress of precision oncology. We are confident that the published comprehensive and novel insights will motivate further translational and clinical cancer research, leading to the development of tailored therapeutic cancer treatments and improving clinical outcomes. They will certainly boost the ascending scientific trajectory of Onco.