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PubMed2025

Notch pathway defines an aggressive and immune-suppressive phenotype associated with checkpoint inhibitor resistance in pan-gastrointestinal adenocarcinomas.

The Notch pathway regulates the homeostasis and tumorigenesis of gastrointestinal epithelium. Given its roles in cancer stem cell capacity and cancer immunity, we hypothesized that Notch activation can predict poor prognosis and resistance to immune checkpoint inhibitors (ICIs) in gastrointestinal adenocarcinoma (GIAC). The mRNA expression and genomic alterations of Notch pathway were characterized in esophagus (ESAD), stomach (STAD), colon (COAD), or rectum (READ) adenocarcinomas from The Cancer Genome Atlas (TCGA) dataset. The prognostic model (mRNA-score) was constructed using the TCGA dataset (the training set) and was validated in 3 independent sets (GSE19417 [ESAD], GSE84437 [STAD], and GSE40967 [COAD]). The associations of the mRNA-score with drug sensitivity, immune cell infiltration, and immunotherapy efficacy were, respectively, analyzed using the Genomics of Drug Sensitivity in Cancer (GDSC) database, the TCGA dataset, and multiple clinical cohorts including GSE165252, PRJEB25780, IMvigor210, and CheckMate-009/010/025. Notch pathway genes exhibited conserved genomic/transcriptomic features across four GIAC subtypes. Three pan-GIAC clusters were determined by unsupervised clustering, and the cluster with higher expression of the Notch pathway genes had shorter overall survival (OS), immunosuppressive microenvironment, and higher scores of the signatures concerning angiogenesis, cell cycle, PI3K-AKT-mTOR, TGF-β, glycolysis, etc. A prognostic algorithm (mRNA-score) was constructed, which was correlated with poor OS in the training set (TCGA, P < 0.001) and three validation sets (GSE19417, P = 0.025; GSE84437, P = 0.001, GSE40967, P = 0.007). A high mRNA-score was linked with more "resting"/ "anti-inflammatory" rather than "activated"/ "pro-inflammatory" tumor-infiltrating immune cells and ICI resistance in GIACs (GSE165252, P = 0.047; PRJEB25780, P = 0.047) and other solid tumors such as urothelial carcinoma and clear cell renal cell carcinoma. Our findings demonstrate the utility of the Notch pathway in predicting prognosis and ICI resistance. Further studies are warranted to explore the efficacy of Notch inhibitors as immunotherapeutic adjuvants to overcome ICI resistance.

Humans↗

PubMed2025

ZNF180 modulates tumor intrinsic immunotherapy resistance in melanoma through driving plasticity.

BACKGROUND: Based on our previous study, we have identified ZNF180, a zinc finger protein, as a pro-tumorigenic regulator in primary melanoma and a marker for poor prognosis. Herein, we report that ZNF180-regulated pathway, hence ZNF180-regulome, underlies resistance towards immune checkpoint inhibitions (ICIs). METHODS: To investigate regulatory roles of ZNF180 to confer these immune suppressive phenotypes, we performed ZNF180 knock-down in melanoma cells in vitro with different genetic backgrounds, namely A375 (BRAF-mutant) and SKMEL147 (NRAS-mutant) cells, and performed RNA- and ATAC-sequencing. We performed integrative analysis of RNA- and ATAC-sequencing data with publicly available sequencing data from ICI-treated cohorts to construct comprehensive model of ZNF180-regulome and its impacts on immune microenvironment. Further, we performed ZNF180 silencing in immune competent Yumm1.7 murine model to confirm the changes in immune microenvironments. RESULTS: ZNF180-regulome was predictive of ICI responses in independent bulk sequencing cohorts, and ZNF180+ tumors persisted after the therapy with immune-suppressive features such as MHC-I loss and CD155 expressions, the primary ligand to TIGIT inhibitory receptor. Further, ZNF180 silencing revealed its regulations on AP-1 transcription factors to drive melanoma reprogramming towards de-differentiated MITFlowAXLhigh cells, an established melanoma subtypes associated with recurrence and ICI resistance. In tandem, we observed that ZNF180+ tumor neighborhood significantly excluded with CD4 T-cells in metastatic tumor, and its silencing in immune competent murine model increased CD4 helper T-cell infiltrations with significant tumor regression in vivo. CONCLUSION: Collectively, these results indicate ZNF180 is a tumor intrinsic regulator of melanoma plasticity to drive de-differentiated phenotypes with immune-suppressive features including loss of immunogenicity, T-cell inhibitory signals through TIGIT/CD155 checkpoint and exclusion of CD4 helper T-cells. As ZNF180-regulome manifests in non-metastatic melanoma in contrast to the current focus of standard-of-care ICI on the metastatic disease, these results establish ZNF180-regulome as a biomarker and novel therapeutic avenue for early-stage, non-metastatic melanoma to intervene ICI resistance.

Immune checkpoint inhibition↗

PubMed2026

Myeloid-Mediated Immunoregulation and Resistance to Immune Checkpoint Inhibitor Therapy Across Squamous Cell Carcinomas: Mechanisms and Reprogramming Strategies.

Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have improved outcomes across squamous cell carcinomas (SCCs) of the head and neck, lung, esophagus, and skin, yet durable responses remain confined to a subset of patients in every subtype. Objective response rates vary substantially across SCCs despite overlapping genomic alterations, comparable tumor mutational burden, and high PD-L1 expression, indicating that tumor-intrinsic biomarkers alone do not explain this variability. Growing evidence points to the tumor immune microenvironment, and in particular the myeloid compartment, as a critical determinant of immunotherapy responsiveness. In this review, we synthesize current evidence on myeloid-mediated immune regulation across SCC subtypes, focusing on tumor-associated macrophages, myeloid-derived suppressor cells/tumor-associated neutrophils, and dendritic cells, and the mechanisms by which these populations impair antigen presentation, restrict T cell infiltration, and sustain immunologically "cold" tumor states. We further examine therapeutic strategies aimed at reprogramming rather than simply depleting suppressive myeloid populations, including radiation therapy, STING agonism, and myeloid-targeted agents (CSF1R, PI3Kγ, and CXCR2 inhibition), each of which has shown encouraging preclinical and early clinical activity in combination with ICI. Collectively, this evidence supports a model in which the myeloid compartment functions as an actionable, convergent determinant of ICI resistance across SCC subtypes, rather than merely a passive biomarker. We propose that through the integration of spatial and single-cell profiling of myeloid states with clinical history it will be possible to predict response to immune checkpoint therapy and personalize myeloid-directed combination strategies, though the specific biomarkers needed to match individual patients to a given myeloid-targeted approach remain to be defined. We further discuss the toxicity considerations associated with both immune checkpoint blockade and radiation-based combination approaches, the early-phase status of most myeloid-targeted agents currently in clinical development, and the extent to which mechanistic insight, derived predominantly from HNSCC, generalizes to squamous cell carcinomas arising at other anatomic sites.

dendritic cells↗

PubMed2025

Tumor microenvironment governs the prognostic landscape of immunotherapy for head and neck squamous cell carcinoma: A computational model-guided analysis.

Immune checkpoint inhibition (ICI) has emerged as a critical treatment strategy for squamous cell carcinoma of the head and neck (HNSCC) that halts the immune escape of the tumor cells. Increasing evidence suggests that the onset, progression, and lack of/no response of HNSCC to ICI are emergent properties arising from the interactions within the tumor microenvironment (TME). Deciphering how the diversity of cellular and molecular interactions leads to distinct HNSCC TME subtypes subsequently governing the ICI response remains largely unexplored. We developed a cellular-molecular model of the HNSCC TME that incorporates multiple cell types, cellular states, and transitions, and molecularly mediated paracrine interactions. Simulation across the selected parameter space of the HNSCC TME network shows that distinct mechanistic balances within the TME give rise to the five clinically observed TME subtypes such as immune/non-fibrotic, immune/fibrotic, fibrotic only and immune/fibrotic desert. We predict that the cancer-associated fibroblast, beyond a critical proliferation rate, drastically worsens the ICI response by hampering the accessibility of the CD8 + killer T cells to the tumor cells. Our analysis reveals that while an Interleukin-2 (IL-2) + ICI combination therapy may improve response in the immune desert scenario, Osteopontin (OPN) and Leukemia Inhibition Factor (LIF) knockout with ICI yields the best response in a fibro-dominated scenario. Further, we predict Interleukin-8 (IL-8), and lactate can serve as crucial biomarkers for ICI-resistant HNSCC phenotypes. Overall, we provide an integrated quantitative framework that explains a wide range of TME-mediated resistance mechanisms for HNSCC and predicts TME subtype-specific targets that can lead to an improved ICI outcome.

Tumor Microenvironment↗

PubMed2025

What is on the Horizon Beyond Platinum and Immunotherapy for Patients With Advanced Non-Small Cell Lung Cancer Without Actionable Genomic Aberrations?

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related death worldwide. While targeted therapy and immunotherapy have transformed first-line management, most patients without actionable genomic alterations (AGAs) will experience disease progression within the first year of their initial treatment. Here, we review pivotal trials, emerging strategies, challenges, and unmet needs for patients with advanced NSCLC without AGAs. Docetaxel with or without ramucirumab is the standard second-line therapy for patients who have progressed after platinum-based chemotherapy and immunotherapy. Targeted therapy is only suitable for patients with specific AGAs. Understanding the hallmarks of cancer immune evasion is key to developing new strategies beyond chemoimmunotherapy. The combination of antiangiogenic agents with immune checkpoint inhibitors (ICIs) has shown mixed results after progression on platinum and ICI. Bispecific antibodies, particularly ivonescimab, have shown encouraging early efficacy in this space. Artificial intelligence-driven pathomics and radiomics tools may help to refine treatment selection in the future. Chimeric antigen receptor T-cell therapy remains investigational. Patients with advanced NSCLC without AGAs who progressed after chemoimmunotherapy have limited treatment options. Novel therapies such as specific antibodies have shown promising results. Future progress will depend on the development of predictive biomarkers and understanding the mechanisms of resistance to ICIs to guide drug development.

Humans↗

PubMed2026

Integrative subtyping by bile acid metabolism identifies CLCA1/UGT2A3/ZG16 as markers of immune dysfunction and poor prognosis in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is the primary driver of cancer-related death and illness across the world. Despite the full-scale shift of the treatment approach for some colorectal cancer patients due to the use of immune checkpoint inhibitors (ICIs), primary resistance still poses a huge challenge to clinicians. Bile acid metabolism is involved in the pathogenesis of CRC. However, its particular function in shaping the tumor immune microenvironment (TIME) and its effect on prognosis and immune treatment response remain unclear. METHODS: Based on the transcriptome and clinical data from The Cancer Genome Atlas-Colon Adenocarcinoma (TCGA-COAD) cohort, we performed unsupervised consensus clustering and classified patients into different molecular subtypes according to bile acid metabolism. We subsequently compared overall survival (OS), immune cell infiltration levels, and differentially expressed genes among the subtypes. In addition, protein-protein interaction (PPI) network and Cox proportional hazards regression were used to identify key hub genes. Finally, the expression of these crucial hub genes was validated in the Gene Expression Omnibus (GEO) cohort and independent clinical patients. RESULTS: The bile-low group showed a significant reduction in OS time (p = 0.0049). The infiltration levels of CD8+ T cells (p < 0.05) and M1 macrophages (p < 0.01) were significantly higher in the bile-low group than in the bile-high group. We identified three key genes-CLCA1, UGT2A3, and ZG16-and found that they all were downregulated in tumor tissues across the TCGA-COAD and GEO datasets, as well as in independent clinical samples. Survival analysis showed that high CLCA1 expression was significantly associated with favorable overall survival (p < 0.001), whereas UGT2A3 (p = 0.23) and ZG16 (p = 0.17) did not reach statistical significance. The three hub genes were negatively correlated with the (TIDE) score (CLCA1: R = - 0.24, p < 0.001; UGT2A3: R = - 0.15, p = 0.0022; ZG16: R = - 0.14, p = 0.0039). CONCLUSION: Our findings suggest that bile acid metabolism could shape the TIME via key genes CLCA1, UGT2A3, and ZG16, and subsequently modify CRC prognosis and immunotherapy responses. These genes may serve as potential prognostic indicators and mechanistic mediators linking bile acid metabolism to T-cell dysfunction, offering insights for future combination strategies targeting the metabolism-barrier-immunity axis.

CLCA1↗

PubMed1977

[Effects of a new cardioselective beta-adrenergic blocker (atenolol) on airway resistance in chronic obstructive disease (author's transl)].

The effect of 4-(2-hydroxy-3-isopropylamino-propoxy)-phenyl acetamide (atenolol, ICI 66 082) (100 mg) on airway resistance (Rt), thoracic gas volume (IGV), pulse rate and blood pressure was tested as a double blind study in 20 patients with chronic obstructive airway disease in comparison to propranolol (80 mg) and placebo. The effect on pulse rate was equipotent, but when using propranolol the mean increase of Rt was larger and increased Rt-values (greater than or equal 1.5 cm H2O/l/sec) were observed more frequently than after atenolol application. These differences were significant for 1 h after application. The augmentation of IGV was significantly larger after propranolol than after atenolol. We conclude that atenolol, in comparison to propranolol, has a relative but no specific cardioselectivity.

Adult↗

PubMed2026

Lipid metabolic reprogramming of tumor-associated macrophages drives resistance to immune checkpoint blockade in lung cancer: a narrative review of mechanisms and therapeutic strategies.

BACKGROUND AND OBJECTIVE: Immune checkpoint inhibitors (ICIs), represented by programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1), have shown remarkable efficacy in non-small cell lung cancer (NSCLC); however, many patients still develop resistance to immunotherapy. Although small cell lung cancer (SCLC) is also an important histological type of lung cancer, NSCLC accounts for the majority of lung cancer cases. Current research on ICI development, first-line treatment efficacy, and the mechanisms of lipid metabolism in tumor-associated macrophages (TAMs) is predominantly focused on NSCLC. In patients with advanced NSCLC, objective response rates (ORRs) with PD-1/PD-L1 inhibitor monotherapy remain limited. Only in patients with high PD-L1 expression [tumor proportion score (TPS) ≥50%] and without sensitizing epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements does the ORR increase to approximately 40-45%. TAMs are a key component of the immunosuppressive tumor microenvironment (TME). Lipid metabolic reprogramming profoundly influences the functional and transcriptional features of TAMs. This review aims to integrate relevant evidence, elucidate how TAM lipid metabolism promotes immunosuppression and resistance to ICIs, and outline potential therapeutic strategies. METHODS: We searched PubMed/MEDLINE, Web of Science, and Scopus for publications up to June 2026 using terms combining lung cancer, TAMs, lipid metabolism, and immune checkpoint blockade/resistance. Mechanistic, translational, and clinically relevant studies were selected by author consensus. KEY CONTENT AND FINDINGS: Lipid uptake, de novo lipogenesis, fatty acid oxidation (FAO), cholesterol remodeling, and eicosanoid metabolism are not independent processes in TAMs. Lipid metabolic reprogramming in TAMs ultimately suppresses type I interferon (IFN-I) signaling, upregulates PD-L1 expression, and impairs the function of CD8+ T cells with stem-like features, thereby establishing an immunosuppressive TME and leading to resistance to ICIs. In lung cancer, hypoxia, high lactate levels, and tobacco exposure further shape the lipid phenotype of TAMs, such as lipid raft enrichment and lipid-laden macrophage subsets like SPP1+ macrophages. Different driver genomic backgrounds differentially impact tumor cell-intrinsic metabolism and the lipid metabolic programs of myeloid cells. In preclinical models, interventions targeting these metabolic axes, including TAM-directed delivery systems, have demonstrated potential therapeutic benefit when combined with anti-PD-1/PD-L1 therapy. CONCLUSIONS: Targeting TAM lipid metabolism to convert immunologically cold tumors into more inflamed, ICI-responsive tumors is a promising strategy to overcome resistance in NSCLC. Identification of predictive biomarkers of therapeutic response and development of cell-selective drug delivery systems come to be major challenges.

Non-small cell lung cancer (NSCLC)↗

PubMed2025

Artificial intelligence-powered spatial analysis of tumor microenvironment in patients with non-small cell lung cancer with acquired resistance to EGFR tyrosine kinase inhibitor.

PURPOSE: This study evaluated the dynamic changes in the tumor microenvironment (TME) in patients with non-small cell lung cancer (NSCLC) and acquired resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) using an artificial intelligence (AI)-powered spatial TME analyzer. We then assessed the predictive efficacy of immune-checkpoint inhibitors (ICIs)-based treatment. EXPERIMENTAL DESIGN: An AI-powered whole-slide image analyzer was used to segment cancer areas (CAs) and cancer stroma and to identify tumor-infiltrating lymphocytes (TILs), tertiary lymphoid structures, fibroblasts, and endothelial cells (ECs) in the tumor tissue. We analyzed 143 NSCLC samples after resistance to EGFR-TKIs from two cohorts: (1) 89 patients treated with ICI monotherapy and (2) 54 patients from the ATTLAS phase III trial comparing atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP) versus pemetrexed plus carboplatin. RESULTS: Post-TKI samples showed reduced TILs in the CA (p=0.045) and increased ECs in the CA (p=0.005) compared with pre-TKI samples. These changes differed according to EGFR mutation subtype. Higher TILs in CA were associated with a better overall response rate (ORR) and progression-free survival (PFS). Similarly, higher EC levels in CA correlated with improved ORR and PFS. In the ATTLAS cohort, these factors were associated with clinical benefits from ABCP, with a significant association with TILs and a marginal association with ECs. CONCLUSION: Our findings suggest that EGFR-TKIs affect the immune landscape of patients with EGFR-mutated NSCLC. Higher TILs or ECs in the CA were significantly associated with a favorable response to subsequent ICI-based treatment. TRIAL REGISTRATION NUMBER: NCT03991403.

Aged↗

PubMed2026

Deconstructing Exceptional Responses to Immune Checkpoint Inhibition in Recurrent or Metastatic Head and Neck Carcinoma: A Site-Specific Clinical-Biological Synthesis.

Background: Recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is an aggressive malignancy with a historically poor prognosis. Although immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have established a new first-line standard of care, durable clinical benefit is restricted to a minority of patients, while primary or acquired resistance remains a major clinical challenge. This narrative review aims to provide a conceptual clinical-biological synthesis of immunotherapy in R/M HNSCC through an anatomical and biomarker-driven lens, with a focus on characterizing potential shared features of "exceptional responders". Methods: A targeted narrative literature search was conducted across PubMed/MEDLINE and to identify key clinical trials and representative clinical reports of exceptional response to ICIs in R/M HNSCC. The literature was not systematically synthesized to construct a conceptual clinical-biological framework of response and resistance. Results: Landmark clinical data confirm durable survival benefits with frontline pembrolizumab-based regimens in selected PDL-1 positive populations compared to historical chemotherapy. Qualitative appraisal of illustrative cases and translational cohorts suggests a potential biological hypothesis: exceptional responders, defined as patients achieving unexpected, multi-year complete radiological, pathological, or metabolic remissions, often align with a favorable confluence of a pre-existing "hot" or inflamed tumor microenvironment, preserved antigen presentation machinery, and elevated antigenic novelty driven by viral oncoproteins (HPV, EBV) or high mutational/indel burdens. Conversely, primary and acquired resistance are conceptually associated with defects in antigen processing, immunosuppressive cellular barriers, and alternative immune checkpoints. Conclusions: Immunotherapy has fundamentally transformed R/M HNSCC management, yet exceptional single-agent responses remain rare. Rather than a definitive or proven biological biomarker, the proposed blueprint represents an integrative hypothesis highlighting the complex interplay of baseline immune inflammation, genomic features, and viral drivers. Translating these observations into broader clinical benefit will require validated biomarker-driven personalization and rationally designed combination regimens.

Epstein-Barr virus (EBV)↗

PubMed2026

Targeting USP22 reprograms the tumor microenvironment and sensitizes KRAS/p53-driven lung cancer to anti-PD-1 immunotherapy.

RATIONALE: Ubiquitin-specific peptidase 22 (USP22), a deubiquitinase and component of the "Death-from-Cancer" 11-gene signature, is overexpressed in multiple malignancies and linked to recurrence, therapy resistance, and poor prognosis. Its role in KRAS/p53-driven lung cancer and the response to immune checkpoint inhibitors (ICIs) remains poorly defined. Here, we investigated USP22 as a potential therapeutic target in KRAS/p53-driven lung cancer. METHODS: A conditional Usp22 knockout (Usp22-KO) was generated in the KRASG12D; p53-/- (KP) mouse model. Cancer progression was monitored by micro-computed tomography (micro-CT). Multiplex immunofluorescence (mIF), RNA sequencing, and spatial transcriptomics profiled cancer and tumor microenvironment (TME) changes. Responses to anti-PD-1/PD-L1 therapies were compared between KP and Usp22-KO KP (KPU-) lung cancers. RESULTS: USP22 was highly expressed in early-stage KRAS/p53-driven mouse lung cancers and strongly correlated with proliferation marker Ki67. Usp22 deletion suppressed cancer growth, prolonged survival, and promoted cancer differentiation. Spatial transcriptomics and mIF revealed reduced CD206+ M2 macrophages, myeloid-derived suppressor cells (MDSCs), TGF-β1, and angiogenesis, along with increased functional CD8+ T cells. Mechanistically, USP22 regulated gene expression and protein stability, reducing c-Myc, PD-L1, TGF-β1, and SPARC upon Usp22 loss. Compared with KP cancer, KPU- and SPARC-knockdown KP cancers showed reduced macrophage chemotaxis and impaired basal- and TGF-β1-induced M2 polarization of RAW264.7 cells, suggesting that TGF-β1 and SPARC downregulation partially contributes to decreased M2 macrophage infiltration in KPU- cancers. Notably, Usp22 loss enhanced the efficacy of anti-PD-L1 and anti-PD-1 therapies in orthotopic and subcutaneous KP lung cancer models, respectively. USP22 and SPARC expression were also strongly correlated in human lung cancers. CONCLUSIONS: USP22 promotes progression and immune evasion in KRAS/p53-driven lung cancer. Targeting USP22 reprograms the TME, suppresses oncogenic signaling, and sensitizes tumors to ICI, establishing USP22 as a promising therapeutic target.

Animals↗

PubMed2026

Pan-cancer single-cell atlas of immunotherapy response identifies ZNF385A as a regulator of immune evasion in small cell lung cancer.

Although immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of solid tumors, response rates in patients with small cell lung cancer (SCLC) remain limited, and acquired resistance is highly prevalent. The underlying mechanisms of this immunotherapy resistance remain to be fully elucidated. Clinically, SCLC typically manifests as an "immune-cold" tumor, characterized by a low abundance of CD8+ T cell infiltration and the rare formation of tertiary lymphoid structures (TLS). While DNA damage repair (DDR) is closely linked to innate immune responses, how DDR networks orchestrate the SCLC immune microenvironment remains obscure. In this study, we integrated single-cell transcriptomic data (comprising 344,447 high-quality cells) from six cancer types (BCC, CRC, HCC, HNSCC, iCCA, and SCLC). Our comparative analysis revealed a fundamental depletion of TLS-associated cellular subpopulations (e.g., CXCL13+ CD8+ T cells, HLA-DRB5+ B cells, and CXCL9+ dendritic cells) in SCLC, which was significantly correlated with aberrant DDR activity. Through high-dimensional weighted gene co-expression network analysis (hdWGCNA), we identified ZNF385A as the core hub gene within the DDR-associated module. ZNF385A is highly expressed in SCLC and is associated with poorer prognosis. In vitro, ZNF385A depletion suppressed SCLC cell proliferation and induced apoptosis, accompanied by R-loop accumulation and activation of cGAS-STING signaling, indicating a potential link between ZNF385A, genomic stability and tumor-intrinsic innate immune signaling. Collectively, these findings identify ZNF385A as a potential regulator associated with TLS deficiency and immune evasion in SCLC.

Immunotherapy resistance↗

PubMed2026

Beyond the "cold" barrier: Redefining the clinical paradigm of immune checkpoint inhibitor therapy in ovarian cancer.

Ovarian cancer remains an immunologically "cold" tumor, with early all-comer immune checkpoint inhibitor (ICI) trials largely negative despite underlying immunogenicity. This review takes a clinician-centric, stage-specific view linking regimen choice, treatment line, and tumor-immune context to observed outcomes. In the neoadjuvant and first-line settings, unselected ICI combinations with chemotherapy and anti-angiogenic agents failed to improve progression-free survival, whereas adding a poly (ADP-ribose) polymerase (PARP) inhibitor to ICI maintenance yielded modest gains in biomarker-enriched cohorts. In recurrent disease, single-agent ICIs produced objective response rates of 8-15%, and most randomized combinations were negative. The phase III KEYNOTE-B96 trial in platinum-resistant disease demonstrated a progression-free survival benefit in the intention-to-treat population and an overall survival benefit in tumors with programmed death ligand 1 (PD-L1) combined positive score ≥ 1 when pembrolizumab was paired with weekly paclitaxel with or without bevacizumab, underscoring the value of an immunomodulatory chemotherapy backbone in earlier lines. Ovarian clear cell carcinoma emerges as an immunotherapy-sensitive, chemo-resistant subtype that warrants dedicated stratification. We explain why single-analyte biomarkers-PD-L1, tumor mutational burden, homologous recombination deficiency/BRCA1/2-have not reliably enriched benefit and outline a multidimensional approach integrating genomic scars (e.g., mutational signature 3), immune functional state (Immunoscore, CD8⁺ tumor-infiltrating lymphocyte density and CD8⁺: regulatory T-cell ratio), and spatial architecture (inflamed, excluded, desert phenotypes). This framework aims to move beyond the all-comer era toward context-informed precision immunotherapy in ovarian cancer.

Humans↗

PubMed2025

The Role of Homologous Recombination Deficiency (HRD) in Renal Cell Carcinoma (RCC): Biology, Biomarkers, and Therapeutic Opportunities.

Renal Cell Carcinoma (RCC) is a common malignancy, often diagnosed incidentally. In recent years, the prognosis of metastatic disease has been improved due to the development of immune checkpoint inhibitors (ICI) and tyrosine kinase inhibitors (TKI) as first-line treatments. However, when progression occurs, the therapeutic options are limited. Understanding crucial biological pathways could lead to a greater understanding of the natural history of the disease, which could help to overcome the mechanism of resistance and to develop new treatments. The clinical significance of homologous recombination deficiency (HRD) in RCC remains to be investigated. To improve the knowledge about this topic, we conducted a narrative review to summarize the current evidence on HRD-related variations and signatures in RCC, together with their prognostic and predictive implications. Preliminary evidence indicates that canonical HRD variants (BRCA1/2) are infrequent in RCC, while broader DNA damage response (DDR) alterations like BAP1, PBRM1, ATM, and SETD2 are more prevalent. Elevated HRD genomic scores in clear-cell RCC correlate with a worse prognosis and an immunologically exhausted microenvironment. From a therapeutic point of view, PARP inhibitor monotherapy has exhibited initial efficacy in small cohorts with high levels of DDR mutation, yet remains investigational for RCC.

Humans↗

PubMed2026

Radiogenomics predicts immune microenvironment heterogeneity and response to combination immunotherapy in hepatocellular carcinoma.

BACKGROUND: The combination of immune checkpoint inhibitors (ICIs) with anti-angiogenic agents is the preferred first-line therapy option for patients with advanced hepatocellular carcinoma (HCC), yet only a subset of patients responds, urging the quest for prediction biomarkers. We aimed to integrate genomics with radiology to propose an immune-derived radiogenomics biomarker of response to such combination immunotherapy and evaluate its added value in clinical context. METHODS: We integrated bulk RNA sequencing (RNA-seq) and proteomics data of 994 HCC patients with single-cell RNA-seq data of 11 samples across multiple datasets to identify an immune-related signature (IRS) that may influence sensitivity or resistance to such combined immunotherapy strategy, followed by verification of selected marker genes using immunohistochemistry and cytological experiments. We then trained/validated a cross-modality radiogenomics biomarker using machine learning based on TCIA database that was further tested in multi-scale independent cohorts covering 754 HCC patients. RESULTS: Integrative multi-omics analysis identifed a parsimonious 2-gene prognostic signature including KPNA2 and SMG5 that was significantly associated with immune heterogeneity and response to combination immunotherapy. Machine-learning pipeline exported the optimal 4-feature radiogenomics biomarker using support vector machine that significantly discriminated prognosis (hazard ratio 1.415–1.890; p < 0.05 for all) and modestly predicted response to ICI plus anti-angiogenic therapy (area under the curve 0.720–0.829) in independent retrospective series across major imaging modalities (computed tomography/magnetic resonance imaging). In a prospective neoadjuvant cohort, this biomarker also showed favorable performance for predicting pathological response and tumor recurrence, accompanied by biological validation through single-cell RNA-seq analysis of pre-treatment biopsies. CONCLUSIONS: Our study provides a cross-device-cross-modal radiogenomics biomarker that can improve patient selection for emerging ICI plus anti-angiogenic therapy with novel potential therapeutic targets in HCC.

Humans↗

PubMed2026

Genomic Profiling, Risk Stratification, and Post-Transformation Treatment Outcomes in Patients with Transformed Small-Cell Lung Cancer: A Multicenter Analysis.

BACKGROUND: Transformed small-cell lung cancer (T-SCLC) is an increasingly recognized resistance mechanism in EGFR-mutant lung adenocarcinoma. This study aimed to identify early predictors of histologic transformation and evaluate post-transformation treatment outcomes. METHODS: We retrospectively collected 163 T-SCLC patients from five Chinese centers. Next-generation sequencing was performed on 60 EGFR-mutant patients, including 47 paired primary-transformed samples. Integrated genomic and clinical analyses were conducted to delineate molecular features and survival outcomes. RESULTS: Among 150 EGFR-mutant patients, the median time to SCLC transformation was 25.8 months and median post-transformation overall survival (OS) was 14.2 months. Clinical and survival data for the 13 EGFR wild-type patients are reported descriptively given the limited sample size. Among 108 treatment-evaluable patients, first-line EGFR-TKI plus chemotherapy, chemotherapy alone, and immune checkpoint inhibitors (ICIs) plus chemotherapy yielded median progression-free survival (PFS) of 6.2, 5.30, and 4.07 months (P = 0.041) and median OS of 21.2, 27.6, and 13.6 months (P = 0.193). In later-line therapy, taxane-based regimens achieved a median PFS of 6.93 months, outperforming camptothecin-based (1.13 months) and other regimens (1.90 months; P = 0.049). High evolutionary diversity was associated with shorter post-transformation OS (6.77 vs. 11.10 months), with restricted cubic spline analysis showing a nonsignificant trend toward a nonlinear association (P = 0.055).Age, RB1/NTRK1 mutation, and secondary T790M mutation were identified as independent risk factors and integrated into a predictive model with high accuracy. CONCLUSIONS: This study establishes a clinically applicable model for early prediction and risk stratification of SCLC transformation. Taxane-based regimens emerge as a promising later-line therapeutic option for T-SCLC.

Humans↗

PubMed1975

Predictive value of various parameters for the antihypertensive effect of the beta blocker ICI 66,082 (1).

The antihypertensive effect of the new beta-blocker, ICI 66,082 was studied in 37 patients with renal or essential hypertension. A daily dose of 75 mg produced a significant antihypertensive effect and a further blood pressure decrease was obtained by increasing the daily dose up to 300 mg; at this treatment level, the antihypertensive effect averaged 29.4/24.0 mm Hg. Increasing the dose from 300 to 600 mg daily did not produce a significant additional blood pressure decrease. Six of the 37 patients retained fluid, producing a loss in the antihypertensive effect. No significant correlation was found between the percentage systolic blood pressure fall and the following parameters determined before therapy: systolic blood pressure and its variability, heart rate (at rest and after stimulation by exercise or isoproterenol), cardiac output and total peripheral resistance, renin concentration (at rest and after stimulation) and urinary excretion of catecholamines and derivates.

Adrenergic beta-Antagonists↗

PubMed2026

Glutathione reductase deficiency potentiates the immunogenicity of ferroptosis and cuproptosis via amplified reactive oxygen species accumulation and cGAS-STING pathway activation.

BACKGROUND: Cancer remains a major therapeutic challenge due to drug resistance and metastasis, processes driven by oxidative stress and redox imbalance. Targeting this vulnerability through ferroptosis (iron-dependent lipid peroxidation) and cuproptosis (copper-driven mitochondrial dysfunction), two ROS-mediated cell death pathways, offers a promising therapeutic strategy. However, clinical translation is hindered by incomplete understanding of their redox regulation and limited immunogenicity. METHODS: A genome-wide CRISPR knockout screen was performed to identify key regulators of ferroptosis. Genetic depletion or pharmacological inhibition of candidate genes was evaluated across multiple cancer cell lines for sensitivity to ferroptosis inducer RSL3 and the cuproptosis inducer elesclomol (Es). Antitumor efficacy was assessed in xenograft, orthotopic, metastatic, and syngeneic mouse models, alone or combined with immune checkpoint inhibitors. Mechanistic studies also examined ROS production, mitochondrial stress, mitochondrial DNA release, cGAS-STING activation, and immune responses within the tumor microenvironment. RESULTS: Glutathione reductase (GSR), a central enzyme maintaining reduced glutathione (GSH) homeostasis, was identified as the top suppressor of ferroptosis. GSR knockout or pharmacological inhibition markedly sensitized diverse cancer cell lines to RSL3-induced ferroptosis, while GSR overexpression conferred resistance. Strikingly, GSR depletion also enhanced sensitivity to cuproptosis triggered by the copper ionophore Es. In multiple in vivo tumor models, GSR inhibition synergizes with RSL3 or Es to suppress tumor growth, inhibit lung metastasis, and prolong survival. Mechanistically, GSR deficiency amplified ROS production, induced mitochondrial stress, and triggered the cytosolic mitochondrial DNA release under ferroptotic or cuproptotic stress, activating the cGAS-STING pathway in vitro and in vivo. This increased inflammatory cytokine production, promoted immunogenic cell death, and enhanced the release of damage-associated molecular patterns (DAMPs), including HMGB1. Together, GSR inhibition combined with a ferroptosis or cuproptosis inducer transformed the tumor microenvironment into a highly immune stimulatory state, thereby enhancing the efficacy of immune checkpoint blockade through increased dendritic cell activation and T-cell infiltration and activation. CONCLUSIONS: GSR represents a key molecular node connecting and modulating ferroptosis and cuproptosis through redox regulation. Targeting GSR amplifies ROS-mediated immunogenic cell death, triggers cGAS-STING activation in cancer cells, and enhances the efficacy of cancer immunotherapy, providing a promising redox-based therapeutic strategy.

Ferroptosis↗