Search Results (1,210)

Background/Objectives: Triple therapy combining targeted therapy (lenvatinib/bevacizumab), immune checkpoint inhibitors (ICIs), and interventional therapy (TACE/HAIC) has shown promising efficacy, but clinical outcomes differ among patients. We developed and tested a prognostic model based on sex, ALBI grade, and ALR to estimate survival in patients with intermediate-to-advanced HCC receiving triple therapy. Methods: This single center retrospective study included 184 intermediate-to-advanced HCC patients between November 2017 and December 2024. The patients enrolled received lenvatinib (n = 88) or bevacizumab (n = 96) plus PD-1/PD-L1 inhibitors and interventional therapy. The risk scoring model was derived from univariate Cox regression, LASSO Cox regression, and multivariate Cox regression analyses that were screened for independent prognostic factors. The median risk score defined the cutoff for separating patients into two risk subgroups (high- and low-risk). Overall survival (OS) across subgroups was evaluated and compared by Kaplan–Meier analysis and log-rank test. Model performance was evaluated using the C-index, time-dependent AUC at 6, 12, and 24 months, calibration curves, the Brier score, and decision curve analysis, with internal validation performed via Bootstrap resampling. Results: Multivariate analysis identified male sex, ALBI grade 3, and a high ALR level as independent risk factors of poorer OS. The resulting risk model showed a C-index of 0.62. Moreover, the median OS differed significantly between the two risk groups (p < 0.001). The model displayed moderate discrimination, with AUCs of 0.66, 0.66, and 0.74 at 6, 12, and 24 months. Calibration and the Brier score showed reasonable agreement and acceptable prediction errors. No interaction between risk factors and treatment type was observed (p > 0.05), indicating model applicability to both lenvatinib and bevacizumab-based regimens. Conclusions: A prognostic model integrating sex, ALBI grade, and ALR can offer some capacity to stratify survival risk in intermediate-to-advanced HCC patients. However, its overall discriminative performance is limited, and further validation in larger and external cohorts is needed to confirm its clinical value. Full article

Background: Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with poor survival rates of late-stage disease. While immune checkpoint blockade (ICB) therapy has transformed treatment for mismatch repair-deficient (MMRd)/microsatellite instability-high (MSI-H) tumors, most CRC cases are mismatch repair-proficient (MMRp)/microsatellite-stable (MSS) and derive little to no benefit from current immunotherapy regimens. Tumor-associated macrophages (TAMs) constitute a significant component of the tumor microenvironment (TME) and exhibit a phenotypic gradient between pro-inflammatory (M1-like) and anti-inflammatory, immunosuppressive (M2-like) states. Although their polarization status is increasingly recognized as a key modulator of immunotherapy efficacy in CRC, a comprehensive synthesis of the literature regarding macrophage polarization and its relevance to improving CRC immunotherapy remains lacking. Methods: A systematic literature search was conducted across PubMed, EMBASE, and ScienceDirect from inception to December 2025 using terms encompassing macrophages, immunotherapy, immune checkpoint expression, colorectal cancer, and microsatellite stability status. Title, abstract, and full-text screening were performed independently by multiple authors. Sixty-five studies were included following PRISMA guidelines. The protocol was prospectively registered on PROSPERO (ID: CRD420251244320). Results: Three key themes were identified: (1) macrophage-mediated mechanisms of resistance to ICB, including M2 polarization driven by the PI3Kγ, STAT3, mTOR, and SIRT-1 axes, immunosuppressive cytokine production (IL-10, TGF-β), and altered immune checkpoint ligand expression; (2) macrophage polarization status and associated biomarkers as prognostic indicators of therapeutic response; (3) emerging macrophage-targeted therapeutic strategies in ongoing clinical trials, including CSF1R inhibitors, CD40 agonists, CD47/SIRPα blockade, and STING agonists. Conclusions: TAM polarization is a critical determinant of immunotherapy resistance and patient prognosis in CRC. Macrophage-targeted strategies, particularly M2-to-M1 repolarization approaches used in combination with existing ICB regimens, represent a promising avenue for expanding immunotherapy efficacy beyond MSI-H disease. Further translational research and randomized controlled trials are needed to validate these targets clinically. Full article

Cutaneous Melanoma is a biologically heterogeneous malignancy. Although recent therapeutic advances have improved survival, durable remissions remain elusive for many patients. Surgical excision with stage-appropriate margins and selective nodal staging remains the cornerstone of curative-intent management. In contrast, conventional cytotoxic chemotherapy now plays a limited, largely palliative role given its modest efficacy and substantial toxicity. Targeted therapy with BRAF/MEK inhibitors has improved outcomes in patients with BRAF V600-mutant melanoma, resulting in rapid tumor regression and meaningful survival benefits. However, long-term disease control is frequently compromised by adaptive resistance, commonly driven by MAPK pathway reactivation or compensatory PI3K/AKT signaling. In parallel, immune checkpoint inhibitors targeting PD-1, CTLA-4, and emerging pathways have reshaped treatment across disease stages, enabling deep and sometimes durable responses. Despite this progress, primary and acquired resistance, as well as acute and chronic immune-related toxicities, continue to pose significant clinical challenges. Current therapeutic strategies focus on rational combinations of targeted therapy, checkpoint blockade, IL-2-based approaches, oncolytic viruses, and adoptive cell therapies such as tumor-infiltrating lymphocytes to enhance response depth and durability. However, these intensified regimens carry increased toxicity risks, highlighting the need for improved patient selection and monitoring. Overall, emerging evidence supports a paradigm shift toward optimized treatment sequencing, response-adapted surgical strategies, and biomarker-guided personalization to maximize clinical benefit while minimizing toxicity. Full article

Pancreatic ductal adenocarcinoma (PDAC) remains among the most therapeutically intractable malignancies, with a 5-year survival rate of approximately 10% and near-universal resistance to immune checkpoint inhibitor (ICI) therapy. This refractoriness arises from the convergence of pronounced intratumoral heterogeneity (ITH) and a profoundly immunosuppressive tumor microenvironment (TME), which together configure PDAC as a prototypical immune-excluded tumor. Beyond low tumor mutational burden, PDAC exhibits layered genetic, epigenetic, transcriptional, and metabolic heterogeneity that enables rapid adaptation and immune evasion under selective pressure, while dense desmoplastic stroma, cancer-associated fibroblasts (CAFs), and immunosuppressive immune populations collectively impose formidable physical and immunologic barriers to antitumor immunity. In this review, we synthesize multi-omics, spatial transcriptomic, and immunologic evidence to elucidate how ITH and the TME dynamically interact to reinforce immune resistance. We examine reciprocal crosstalk mechanisms—including immune-driven clonal selection, interclonal cooperation, metabolic niche specialization, and metabolic–epigenetic coupling—and discuss emerging platforms such as single-cell spatial omics, patient-derived organoid immune co-culture systems, and longitudinal circulating tumor DNA monitoring that enable high-resolution mapping of ITH–TME dynamics. Finally, we evaluate ITH–TME-guided combination therapeutic strategies targeting oncogenic drivers, stromal architecture, myeloid suppression, and metabolic checkpoints, and propose a prioritized framework for near-term and speculative clinical translation in PDAC. Full article

Cholangiocarcinoma (CCA) is an aggressive and molecularly heterogeneous malignancy characterized by a profoundly immunosuppressive tumor microenvironment (TME) and historically limited therapeutic options. Recent advances have redefined the treatment paradigm, with phase III trials establishing chemoimmunotherapy as a standard of care and multi-omic profiling elucidating the interplay between tumor genomics, stromal architecture, and immune regulation. Despite these gains, durable clinical benefit remains confined to a minority of patients, reflecting convergent mechanisms of primary and acquired resistance—including immune exclusion, myeloid-dominant suppression, and genotype-driven “cold” tumor states. In this review, we synthesize emerging insights into the immune landscape of CCA, integrating data from single-cell, spatial, and translational studies to define the cellular and molecular circuits governing immune evasion. Beyond canonical biomarkers such as mismatch repair and microsatellite status, we highlight how spatial organization of immunity—in particular, tertiary lymphoid structures, dynamic myeloid and stromal interactions, and pathway-level features—shape immunotherapy responsiveness. We also examine how tumor-intrinsic alterations, including IDH1 mutation, FGFR2 fusions, KRAS activation, and MTAP loss, define distinct immunologic phenotypes with direct implications for immunotherapeutic response and biomarker-driven patient selection. We evaluate the expanding clinical trial landscape of immunotherapy in CCA and more broadly in BTC, including adoptive cell therapies and cancer vaccines. Together, these advances position CCA as a paradigm of how tumor genotype and microenvironment co-evolve to define immunotherapy sensitivity and resistance. Full article

Immune checkpoint inhibitors (ICIs) show promise in cancer but have limited efficacy in ovarian cancer. This study compared combinations of the PD-1/PD-L1 inhibitor with anti-LAG-3, anti-TIM-3, or anti-CTLA-4 to identify the most effective regimen by assessing T-cell CD8/CD4 ratios and cytokine production. T cells isolated from ovarian cancer tissues (mean 3.8 × 10⁸ cells) were stimulated and treated with the PD-1/PD-L1 inhibitor alone or combined with anti-LAG-3, anti-TIM-3, or anti-CTLA-4. Flow cytometry measured CD8/CD4 expression; ELISAs quantified TNF-α, IL-6, and IFN-γ. Anti-PD-1 monotherapy produced no significant change in CD8/CD4 ratio (1.36 ± 0.43 vs. 1.41 ± 0.36) or cytokine levels. Combination therapy with PD-1/PD-L1 inhibitor + anti-CTLA-4 induced the largest increase in CD8/CD4 ratio (3.69 ± 1.33, p < 0.001) compared with PD-1/PD-L1 inhibitor alone; increases were smaller for PD-1/PD-L1 inhibitor + anti-LAG-3 (2.11 ± 0.63, p = 0.009) and PD-1/PD-L1 inhibitor + anti-TIM-3 (1.87 ± 0.48, p = 0.026). TNF-α rose significantly only with PD-1/PD-L1 inhibitor + anti-CTLA-4 (106.69 ± 45.42 pg/mL, p = 0.008), not with PD-1/PD-L1 inhibitor + anti-LAG-3 (72.46 ± 31.79 pg/mL, p = 0.231) or PD-1/PD-L1 inhibitor + anti-TIM-3 (82.06 ± 33.63 pg/mL, p = 0.074). IFN-γ increase was greater with PD-1/PD-L1 inhibitor + anti-CTLA-4 than with PD-1/PD-L1 inhibitor + anti-LAG-3 (p = 0.026). In conclusion, dual PD-1/PD-L1 and CTLA-4 blockade induced concomitant increases in T-cell CD8/CD4 proportions and cytokine levels compared to monotherapy or alternative ICI pairings. These descriptive ex vivo observations offer preliminary evidence of altered immune profiles, highlighting this combination as a candidate for further functional validation. Full article

Background/Objectives: Extramedullary disease (EMD) is an aggressive and treatment-resistant manifestation of multiple myeloma with limited therapeutic options, particularly in heavily pretreated patients. Methods: We conducted a retrospective study to evaluate the efficacy and safety of concurrent immune checkpoint inhibitors (ICIs) and radiation therapy (RT) in patients with EMD treated at Hackensack University Medical Center and John Theurer Cancer Center between January 2016 and May 2025. Patients were included if they had confirmed EMD and received nivolumab or pembrolizumab with concurrent RT. Results: A total of 21 patients were included, representing a high-risk cohort with a median of 6 prior lines of therapy (range 2–13), including 47.6% triple-class refractory and 19.0% penta-refractory disease. The overall response rate (ORR) was 47.6%, with a clinical benefit rate of 57.1%. Despite these responses, median progression-free survival (PFS) and overall survival (OS) were 4 and 12 months, respectively. Notably, two patients achieved complete responses with nivolumab and RT early in their treatment course following cellular therapy and remain disease-free at last follow-up. The combination of ICIs and RT was generally well-tolerated, with manageable immune-related adverse events and no treatment-related deaths. Conclusions: These findings suggest that concurrent ICI and RT may provide a signal of treatment responses in a subset of patients with advanced EMD, although durability remains limited. Further prospective studies are warranted to further define the role of this combination and identify patients most likely to benefit. Full article

Background: Immune checkpoint inhibitors have significantly improved survival in metastatic melanoma. Combination nivolumab plus ipilimumab demonstrated superior efficacy in randomized trials, including CheckMate 067, but data beyond the first-line setting remain limited. This study evaluated real-world outcomes and predictors of response across different lines of therapy, with an exploratory comparison between first- and second-line use. Methods: This retrospective single-center study included patients with metastatic melanoma treated with nivolumab plus ipilimumab as first- or second-line therapy at Moscow City Oncology Hospital No. 62 between September 2015 and October 2023. Eligible patients had histologically confirmed melanoma and received at least one cycle of dual immune checkpoint blockade. Clinical and demographic data were extracted from electronic medical records. The primary endpoints were progression-free survival (PFS) and overall survival (OS); secondary endpoints included objective response rate (ORR) and safety. Survival outcomes were estimated using the Kaplan–Meier method and compared using the log-rank test. Multivariable Cox proportional hazards models adjusted for clinically relevant covariates were applied to evaluate the association between treatment line and survival outcomes. Additional prognostic analyses were performed using backward stepwise multivariable Cox regression. Results: Median follow-up was 18.2 months (IQR, 6.7–30.4). Median PFS in the overall cohort was 7.9 months (95% CI, 4.2–11.5), and median OS was not reached (NR); 5-year OS: 50%. The ORR was 45.8%, including 15.1% complete responses. Median PFS was 9.0 months (95% CI, 5.0–12.9) in first-line and 6.1 months (95% CI, 3.4–8.8) in second-line patients. Median OS was NR in the first-line cohort and was 30.5 months (95% CI: NR) in the second-line cohort. In exploratory analyses, OS did not differ significantly between patients treated in the first-line (n = 141) versus second-line setting (n = 63) (p = 0.848). After adjustment for clinical and demographic characteristics, line of therapy was not associated with OS (HR 0.93; 95% CI, 0.58–1.50; p = 0.762). Immune-related adverse events were associated with longer PFS (HR 0.66; 95% CI, 0.46–0.93), although this may reflect time-dependent bias. Conclusions: Nivolumab plus ipilimumab demonstrated clinically meaningful activity in both first- and second-line settings. Outcomes were numerically lower than in clinical trials, consistent with broader real-world populations. In exploratory analyses, OS did not differ significantly between treatment lines after adjustment for clinical and demographic characteristics. These findings should be interpreted with caution given the retrospective design and potential sources of bias. Full article

Head and neck squamous cell carcinoma (HNSCC) remains one of the most aggressive and heterogeneous malignancies worldwide, characterized by high rates of locoregional recurrence, metastatic dissemination, and therapeutic resistance. Angiogenesis plays a central role in tumor progression by supporting vascular remodeling, hypoxia adaptation, invasion, immune evasion, and metastatic spread. In HNSCC, angiogenic activation is regulated through complex interactions involving hypoxia-inducible factors, vascular endothelial growth factor (VEGF) signaling, stromal remodeling, inflammatory pathways, and epigenetic mechanisms within the tumor microenvironment. Recent evidence has also highlighted the role of non-coding RNAs, particularly microRNAs, and exosome-mediated communication in modulating angiogenic and immune-related signaling pathways. Although antiangiogenic therapies, including monoclonal antibodies and tyrosine kinase inhibitors, have demonstrated biological activity in HNSCC, their clinical efficacy remains limited by tumor heterogeneity, adaptive resistance mechanisms, toxicity, and the lack of validated predictive biomarkers. Several emerging therapeutic strategies are under preclinical or early clinical investigation in HNSCC, including miRNA-based approaches, nanoparticle-assisted delivery systems, vascular normalization concepts, and combinations with immune checkpoint inhibitors; however, robust clinical evidence for most of these strategies remains limited, and their translation to routine practice requires further validation. This review provides a comprehensive overview of the molecular mechanisms regulating angiogenesis in HNSCC and critically discusses current and emerging pharmacological strategies targeting these pathways. Particular emphasis is placed on VEGF/VEGFR signaling, the integration of miRNA and exosome biology, resistance mechanisms, and translational perspectives for biomarker-guided personalized therapy. The novelty of this review lies in the systematic integration of miRNA- and exosome-mediated angiogenic regulation, therapeutic resistance pathways, and precision medicine strategies into a unified pharmacological framework, addressing gaps not fully covered by prior reviews focused primarily on VEGF-targeted agents. Full article

Background: Programmed death-1 (PD-1) inhibitors have significantly improved survival outcomes in melanoma; however, questions persist regarding comparative efficacy across regimens and the predictive value of PD-L1 expression as a biomarker. We therefore performed a meta-analysis evaluating outcomes according to PD-L1 expression status using the most recent follow-up data from each study. Methods: A systematic search was conducted in PubMed, Cochrane and ClinicalTrials.gov from 1 January 2010 to 1 April 2025 for phase II and III randomized clinical trials (RCTs) investigating PD-1 inhibitors as monotherapy or combined with other immune checkpoint inhibitors (ICIs) or targeted therapy in the adjuvant/metastatic setting. Pooled estimates were calculated with random-effects models, and risk of bias was assessed using the Cochrane RoB 2 tool. The present meta-analysis was performed following PRISMA guidelines and was registered in PROSPERO (ID: CRD420251090090). Results: Fifteen RCTs including 9979 patients were included. In the overall analysis, PD-1 inhibitors were associated with significantly improved overall survival (OS, HR = 0.75, 95% CI: 0.66–0.86) compared with control treatments. In the unresectable or metastatic setting, progression-free survival (PFS) was also significantly improved (HR = 0.61, 95% CI: 0.49–0.76). Survival benefits were observed in both PD-L1-positive and PD-L1-negative tumors, with improved PFS in PD-L1-positive (HR = 0.63, 95% CI: 0.48–0.83) and PD-L1-negative patients (HR = 0.58, 95% CI: 0.44–0.77), as well as improved OS in PD-L1-positive (HR = 0.69, 95% CI: 0.59–0.80) and PD-L1-negative patients (HR = 0.79, 95% CI: 0.67–0.93), without evidence of effect modification by PD-L1 expression. PD-1 inhibitor-based regimens were not associated with a statistically significant increase in grade 3–4 treatment-related adverse events (RR = 1.13, 95% CI: 0.71–1.79); however, heterogeneity was substantial (I² = 96.0%). Conclusions: PD-1 inhibitor-based therapies significantly improve survival outcomes in advanced melanoma across PD-L1 subgroups. No clear evidence of differential treatment benefit according to PD-L1 expression was observed, suggesting limited utility as a standalone predictive biomarker. Further studies integrating molecular and immune profiling are warranted to optimize individualized treatment selection. Full article

Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer-related death worldwide, and first-line systemic treatment has shifted toward immune checkpoint inhibitor (ICI)-based combinations. Response is heterogeneous, and mechanistic interpretation has lagged behind clinical practice, leaving open the question of why some tumors respond while others do not. This review uses the cancer immunity cycle as an HCC-specific scaffold to map where anti-tumor immunity fails—across priming, trafficking, suppressive myeloid or stromal, and metabolic-hypoxic barriers—and interpret combination strategies and resistance through the dominant barrier each tumor presents. ICI monotherapy rescues only specific failure points within the cycle. Combination regimens may be more effective when they are matched to one or more dominant barriers, whereas response may fail when the selected partner addresses only a secondary barrier while the dominant ecological constraint remains intact. Resistance can be similarly organized into tumor cell autonomous, microenvironmental, treatment-induced, and etiology-specific layers, with disease etiology shaping both baseline immune ecology and therapy-context vulnerability. A mechanism-based, biomarker-guided, and etiology-aware framework may help move the field from broad empiricism toward precision immunotherapy, but it should be viewed as a conceptual and translational organizing model that requires prospective testing in biomarker-stratified studies. Full article

Dysregulation of the c-Myc oncogene is a pivotal event in leukemia pathogenesis and therapy resistance. This review synthesizes current evidence, illustrating that c-Myc drives leukemogenesis by enhancing proliferation, inhibiting apoptosis, and upregulating immune checkpoints like PD-L1. Its overexpression is linked to poor treatment outcomes across various leukemia subtypes. Directly targeting c-Myc remains challenging; however, indirect epigenetic modifiers (BET inhibitors), transcriptional disruption (CDK9 inhibitors), and combination therapies emerge as promising strategies to suppress its oncogenic activity and overcome resistance, paving the way for improved clinical management. Full article

Triple-negative breast cancer (TNBC), characterized by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, is a highly aggressive molecular subtype with high recurrence and metastasis rates. Due to the absence of reliable molecular targets, surgery combined with chemotherapy remains the mainstay of clinical treatment. In recent years, immunotherapy has provided new strategies for TNBC management. Immune checkpoints are key regulatory molecules that maintain immune homeostasis, and blocking these checkpoints can restore T cell activity and enhance tumor cell killing. Immune checkpoint inhibitors (ICIs) have demonstrated clinical benefit, particularly in combination with chemotherapy for patients with locally advanced or metastatic TNBC. This review focuses on immune checkpoint–based immunotherapy in TNBC, providing an overview from mechanistic insights to clinical applications and emerging therapeutic strategies. In addition to ICIs, we discuss alternative approaches, such as bispecific antibodies, antibody–drug conjugates (ADCs), chimeric antigen receptor T cell (CAR-T) therapy, tumor vaccines, and oncolytic viruses (OVs), highlighting their current research progress and clinical applications in TNBC treatment. Full article

The adoption of neoadjuvant immune checkpoint inhibitor (ICI)-based chemoimmunotherapy has fundamentally transformed the operative landscape of resectable non-small cell lung cancer (NSCLC). Surgeons are now routinely confronted with ICI-altered tissue planes characterized by hilar fibrosis, vascular friability, and disrupted lymph node architecture. Simultaneously, robotic-assisted thoracic surgery (RATS) has consolidated its position as the dominant minimally invasive platform for pulmonary resection, accounting for the majority of lobectomies and segmentectomies performed at high-volume centers in 2023. Whether RATS confers specific technical advantages in this increasingly complex operative context remains incompletely characterized. We conducted a structured narrative review of published evidence, synthesizing data from randomized controlled trials, prospective cohorts, national registry analyses, and emerging technology reports addressing RATS in the setting of neoadjuvant ICI-based therapy for NSCLC. A systematic literature search was conducted across PubMed and EMBASE using predefined search terms. Available evidence, though largely retrospective and limited by small sample sizes, consistently demonstrates that RATS after neoadjuvant chemoimmunotherapy is technically feasible and oncologically sound, with R0 resection achievable in virtually all cases. The enhanced three-dimensional visualization, tremor filtration, and instrument degrees of freedom afforded by robotic platforms appear particularly advantageous in the setting of dense hilar adhesions and fragile pulmonary vasculature. Lymph node yield, a recognized robotic advantage, is preserved or enhanced despite post-ICI fibrosis. Pooled conversion rates to thoracotomy, derived from post hoc surgical analyses of ICI trial populations rather than trials designed to measure conversion, are higher than for upfront resection; available retrospective single-center data, including one direct RATS-versus-VATS comparison, suggest lower conversion rates with RATS in experienced hands, though this conclusion requires prospective validation. Emerging platform integrations, including combined robotic bronchoscopy and thoracoscopic surgery, single-port systems, and artificial intelligence-assisted anatomical navigation, are poised to further extend the reach of minimally invasive surgery in this challenging clinical scenario. In experienced centers, RATS appears to offer a technically favorable minimally invasive platform for pulmonary resection after neoadjuvant ICI-based therapy, with potential advantages over VATS in managing immunotherapy-altered anatomy; however, this conclusion is derived from retrospective series and should be interpreted cautiously pending prospective comparative data. Prospective multicenter trials with standardized surgical endpoints are urgently needed. Full article

Background/Objectives: Hepatocellular carcinoma (HCC) is challenging to treat with chemotherapy. Immunotherapy has shown moderate responses in inflammatory and immunosuppressive tumor environments. Hepatic cytochrome P450 monooxygenases (CYPs) play a crucial role in xenobiotic and drug metabolism, as well as lipid and steroid metabolism. We aimed to investigate whether CYP expression and various parameters of the innate and adaptive immune system are prognostic factors for the survival of HCC patients. Methods: HCC biopsies (n = 370) from The Cancer Genome Atlas (TCGA) database were analyzed using Kaplan–Meier statistics and the KMPlotter algorithm. Parameters such as immune cell infiltration, DNA mutation rates, and neoantigen load were selected for survival analysis and subjected to hierarchical cluster analysis. The expression of candidate CYP genes in tumors was compared to that in normal liver tissues. Furthermore, tumor infiltration of innate immune cells (basophilic and eosinophilic granulocytes, natural killer cells), adaptive immune cells (CD4+ memory and CD8+ cytotoxic T cells, regulatory T cells, type 1 and type 2 helper T cells), and mesenchymal stem cells was examined. Results: High expression of CYP19A1 and CYP26B1 was associated with shorter survival, whereas high expression of CYP3A5, CYP3A43, CYP7A1, and CYP27A1 was linked to longer survival. Mutation rates combined with CYP expression showed a correlation with five out of six CYP genes, while a high neoantigen load produced less definitive results. A specific cluster exhibiting high CYP expression and immune cell counts or mutation/neoantigen rates was associated with shorter survival, while another cluster was linked to longer survival. Conclusions: CYPs involved in the metabolic regulation of HCC, including CYP3A5, CYP3A43, CYP7A1, CYP19A1, CYP26B1, and CYP27A1, were found to have prognostic value for patient survival. Combined signatures that include CYP expression, mutational rates, and immune cell infiltration into tumors further enhanced the prognostic value for patient survival. This suggests that CYPs may influence the creation of a tumor-specific metabolic microenvironment that impacts immune functions. These combined signatures could be utilized for patient stratification to personalize tumor treatment and develop novel combination therapies aimed at optimizing treatment outcomes, such as combining transarterial chemoembolization (TACE) with immune checkpoint inhibitors. Full article