Search Results (103)

Epithelial ovarian cancer (EOC) remains one of the most lethal gynecologic malignancies, largely owing to advanced-stage presentation, high rates of relapse, and the eventual emergence of therapeutic resistance. Despite the transformative success of immune checkpoint inhibitors (ICIs) across multiple solid tumors, their clinical impact in ovarian cancer has been comparatively modest. This literature review provides a comprehensive synthesis of recent advances in ICI strategies for ovarian cancer (OC), with particular emphasis on phase II and III clinical trials evaluating programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte–associated protein 4 (CTLA-4), and T cell immunoglobulin and mucin-domain-containing-3 (TIM-3)-directed therapies. Accumulating evidence indicates that PD-1/PD-L1 monotherapy yields limited clinical activity in unselected OC populations, with low objective response rates and minimal survival benefit. Dual checkpoint blockade with PD-1 and CTLA-4 inhibitors demonstrates enhanced antitumor activity, particularly in clear cell ovarian carcinoma (CCOC), albeit at the expense of increased immune-related toxicity. Large randomized trials incorporating ICI into first-line chemotherapy or maintenance settings have largely failed to improve outcomes in biomarker-unselected cohorts. Available evidence demonstrates that combinatorial approaches integrating ICI with anti-angiogenic agents, PARP inhibitors, or neoadjuvant chemotherapy provide modest benefit in selected molecular and histologic subgroups. Early-phase investigations of TIM-3–targeting strategies further expand the immunotherapeutic landscape, although clinical efficacy remains preliminary. Current evidence underscores that OC is not uniformly responsive to immunotherapy and that rational combination strategies, biomarker-driven patient selection, and improved understanding of tumor immune microenvironment heterogeneity are essential to unlocking the full therapeutic potential of ICI in this disease. Full article

Immunotherapy with immune checkpoint inhibitors (ICIs) has represented a major breakthrough in the treatment of multiple solid and hematological malignancies, significantly improving survival and tumor control. However, the blockade of immune regulatory pathways such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) is associated with the development of immune-related adverse events, among which immune-mediated colitis (IMC) constitutes one of the most relevant gastrointestinal complications due to its frequency, potential severity, and impact on the continuation of oncologic treatment. IMC typically presents with diarrhea, abdominal pain, and gastrointestinal bleeding, and may progress to severe, life-threatening forms. Its incidence varies according to the type of ICI, and is higher with CTLA-4 inhibitors and particularly elevated with combination therapies. The pathophysiology is complex and multifactorial, involving dysregulated activation of proinflammatory T lymphocytes, impairment of immune regulatory mechanisms, disruption of the intestinal epithelial barrier, and a key modulatory role of the gut microbiota. Diagnosis requires a high index of clinical suspicion and relies on endoscopy with biopsies, given the poor correlation between clinical severity and endoscopic or histological findings. Fecal biomarkers, such as calprotectin and lactoferrin, are useful for risk stratification and disease monitoring. Treatment is based on a stepwise immunosuppressive approach, with corticosteroids as first-line therapy and biologic agents such as infliximab or vedolizumab in refractory cases. Emerging strategies, including fecal microbiota transplantation, offer new therapeutic perspectives. This article provides a comprehensive review of the current evidence on the epidemiology, pathophysiology, diagnosis, and management of IMC, as well as future challenges and opportunities in its clinical management. Full article

Background: Tertiary lymphoid structures (TLSs) play a crucial role in regulating tumor invasion and metastasis and serve as a promising prognostic biomarker in immunotherapy, influencing survival and immune response in multiple cancers. However, existing studies rely on limited gene signatures to assess TLSs, and there remains a lack of comprehensive TLS-related features for pan-cancer prognosis or immunotherapy response prediction. Methods: Based on published TLS gene signatures, mutation data, and expression profiles from 33 tumor types in TCGA, along with data from 15 immune checkpoint blockade (ICB) cohorts, we first systematically evaluated six TLS gene signatures in relation to immune-related indicators and assessed their predictive and prognostic performance across tumors and immunotherapy. Subsequently, using meta-analysis, we constructed a de novo TLS-related gene feature set, termed predictTLS, designed to predict ICB efficacy and prognosis. The rationality and effectiveness of predictTLS were validated using internal validation sets, single-cell transcriptomic, and spatial transcriptomic data. Results: The evaluation revealed associations between TLS gene signatures and key immune-related indicators. The newly constructed predictTLS feature set demonstrated effectiveness in predicting both ICB therapy outcomes and patient prognosis across the analyzed cohorts. Validation across internal datasets, single-cell profiles, and spatial transcriptomics supported the robustness and biological relevance of predictTLS. Conclusions: This study provides a systematically validated, de novo TLS-related gene signature that can serve as a clinical biomarker for predicting immunotherapy response and prognosis in pan-cancer settings. These findings offer new tools for risk stratification and potential therapeutic targeting in tumor immunotherapy. Full article

Background: Immune checkpoint blockade (ICB) has revolutionized lung adenocarcinoma (LUAD) therapy, yet predictive bio-markers remain suboptimal. We hypothesized that BCL2A1 expression in CD8⁺ T cells may reflect immune endurance and complement PD-L1 in predicting ICB response. Methods: Integrating bulk and single-cell RNA-seq across multiple LUAD cohorts, this study performed differential expression, survival, and pathway analyses in a discovery cohort (n = 60) and validated findings across five independent cohorts (n = 126). Results: Single-cell profiling identified BCL2A1 enrichment in tissue-resident memory and proliferating subsets that appeared preferentially expanded in responders; cell–cell communication analysis revealed that BCL2A1^high CD8⁺ T cells exhibited significantly enhanced outgoing signaling capacity (p = 0.0278), with proliferating subsets serving as intra-CD8⁺ coordination hubs and MIF pathway interactions achieving the highest intensity among all axes examined. BCL2A1 was significantly upregulated in responders (FDR < 0.05) and associated with improved ICB survival (HR = 0.43, p < 0.05), but not in non-ICB settings, suggesting treatment-specific prognostic relevance. A tri-marker model integrating BCL2A1, PD-L1 (CD274), and a 27-gene HOT score demonstrated favorable predictive performance (AUC = 0.826 discovery; macro-AUC = 0.774 validation), outperforming PD-L1 alone (AUC = 0.706) and established signatures including TIDE, IPS, TIS, and IFNG. Cross-platform simulations suggested high reproducibility (ρ = 0.982–0.993). Conclusions: These findings suggest BCL2A1 may serve as a bio-marker of CD8⁺ T-cell survival and enhanced intercellular coordination, and its integration with PD-L1 and immune activation markers may yield a reproducible ICB response predictor, pending clinical validation. Full article

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by high immunogenicity and specific immune signatures. Although these molecular features including elevated tumor-infiltrating lymphocytes (TILs) and programmed death-ligand 1 (PD-L1) expression provide a strong rationale for immunotherapy, clinical response remains limited due to multiple mechanisms of immune escape. This review summarizes current and emerging immunotherapeutic strategies in TNBC, including immune checkpoint inhibitors (PDL-1 and cytotoxic T-lymphocyte-associated protein 4 (CTL-4) blockade), adoptive cell therapy (ACT) (chimeric antigen receptor T-cell therapy (CAR-T) and TIL therapy), oncolytic virotherapy, and antibody-based approaches. We also discuss the mechanisms of resistance including DNA damage response alterations, anti-apoptotic signaling, and tumor microenvironment-mediated resistance. Finally, we highlight rational combination strategies, immunotherapy with chemotherapy, targeted therapy, or additional immunotherapies that aim to enhance response to immunotherapy. Ongoing advances in immunotherapy hold significant potential to improve outcomes for patients with TNBC. Full article

Tumor-associated glycosylation is a defining hallmark of cancer, exerting profound effects on multiple aspects of tumor biology. This phenomenon arises from the central role of glycosylation in a wide range of cellular processes and its inherently diverse structural complexity. In cancer cells, aberrant glycosylation often results in the modification of glycoconjugate structures, leading to alterations in cell surface architecture that disrupt cellular homeostasis and signaling pathways. These changes can enhance tumor cell proliferation, invasion, and metastasis by modulating cell adhesion, receptor activation, and intracellular communication. Beyond its direct impact on cancer cells, tumor-associated glycosylation plays a pivotal role in shaping the tumor microenvironment. Aberrant glycan structures influence immune cell infiltration by altering antigen presentation and immune checkpoint interactions, contributing to immune evasion. Additionally, these modifications regulate angiogenesis by affecting endothelial cell function and promoting the formation of aberrant vasculature, which supports tumor growth and metastasis. Glycosylation also mediates tumor–stroma interactions, influencing extracellular matrix remodeling and fibroblast activation, further enhancing cancer progression. This interplay between cancer-associated glycan modifications and their functional roles in tumorigenesis presents a promising therapeutic approach. Unlike conventional treatments, glycan-targeting therapies confer high tumor specificity, operate independently of canonical immune checkpoint targets, and help mitigate immune cell exhaustion. This review explores commonly dysregulated glycan motifs implicated in tumorigenesis and delves into their mechanistic contributions to cancer pathogenesis. We then highlight emerging opportunities for therapeutic intervention, including the development of glycan-targeted therapies and biomarker-driven strategies for cancer diagnosis and treatment. We also outline where glycan-targeted agents (e.g., desialylating biologics, glycomimetics, and anti-glycan mAbs) can complement checkpoint blockade and potentially overcome immune escape. Full article

Background: Lung adenocarcinoma (LUAD) exhibits pronounced cellular and molecular heterogeneity that shapes tumor progression and therapeutic response. Although nucleotide metabolism is essential for sustaining tumor proliferation and coordinating immune interactions, its single-cell heterogeneity and clinical implications remain incompletely defined. Methods: We integrated a publicly available scRNA-seq dataset derived from independent LUAD patients to construct a comprehensive LUAD cellular atlas, identified malignant epithelial cells using inferCNV, and reconstructed differentiation trajectories via Monocle2. Cell–cell communication patterns under distinct nucleotide metabolic states were assessed using CellChat. A nucleotide metabolism-related signature (NMRS) was subsequently developed across TCGA-LUAD and multiple GEO cohorts using 101 combinations of machine learning algorithms. Its prognostic and immunological predictive value was systematically evaluated. The functional relevance of the key gene ENO1 was further verified through pan-cancer analyses and in vitro experiments. Results: We identified substantial nucleotide metabolic heterogeneity within malignant epithelial cells, closely linked to elevated proliferative activity, glycolytic activation, and increased CNV burden. Pseudotime analysis showed that epithelial cells gradually acquire enhanced immune-modulatory and complement-related functions along their differentiation continuum. High-metabolism epithelial cells exhibited stronger outgoing communication—particularly via MIF, CDH5, and MHC-II pathways—highlighting their potential role in shaping an immunosuppressive microenvironment. The NMRS built from metabolism-related genes provided robust prognostic stratification across multiple cohorts and surpassed conventional clinical parameters. Immune profiling revealed that high-NMRS tumors displayed increased T-cell dysfunction, stronger exclusion, higher TIDE scores, and lower IPS, suggesting poorer responses to immune checkpoint blockade. ENO1, markedly upregulated in high-NMRS tumors and functioning as a risk factor in several cancer types, was experimentally shown to promote invasion in LUAD cell lines. Conclusions: This study delineates the profound impact of nucleotide metabolic reprogramming on epithelial cell states, immune ecology, and malignant evolution in LUAD. The NMRS provides a robust predictor of prognosis and immunotherapy response across cohorts, while ENO1 emerges as a pivotal metabolic–immune mediator and promising therapeutic target. Full article

Immunotherapy (IT) and especially immune checkpoint blockade (ICB) changed the therapeutic approach in non-small cell lung cancer (NSCLC). Nevertheless, primary or secondary resistance and a percentage of long responders and survivors have been observed. The aim of this study is to gain a deeper understanding of the complex mechanisms of primary and secondary resistance to IT, involving tumor cells, the tumor microenvironment (TME), and the host, in order to find strategies to overcome it. With this aim in mind, a search for key words has been performed to identify relevant evidence in the literature. The most widely used approach is the combination of IT with chemotherapy (CT) and/or radiotherapy (RT), relying on the synergistic effect on the enhancement of immunogenic cell death. Since a dual role has been observed, a lot of questions are yet to be answered regarding the complex effect of these therapies, especially on the TME. Preclinical and clinical studies investigate the best sequencing and timing of chemoradiation with IT, and the optimal RT volumes, sites, and dose/fractionation regimens to favor immune stimulation over suppression on the TME. Moving forward, multiple agents addressing coinhibitory or costimulatory receptors on immune or tumor cells are under evaluation. The huge potential of combination therapies becoming apparent. Questions regarding targets, selection of patients, and time and sequence of administration are yet to be answered, considering the complex mechanisms of resistance. Dynamic biomarkers to guide personalized treatment decisions are needed. Full article

Circulating tumor DNA (ctDNA) analysis has emerged as a powerful and minimally invasive approach for genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), enabling real-time detection of tumor-derived mutations that guide therapy. Approximately 20% of mCRPC patients harbor alterations in homologous recombination repair (HRR) genes, most commonly BRCA1/2 and ATM, which are actionable with different poly-(ADP-ribose) polymerase inhibitors (PARPIs) used as monotherapy or in combination with androgen receptor signaling inhibitors (ARSIs). A smaller subset of patients with mismatch repair deficiency (MMRd) or microsatellite instability-high (MSI-high) tumors may benefit from immune checkpoint blockade with pembrolizumab. Different FDA-approved liquid biopsy assays detect these actionable alterations when tissue biopsies are unavailable or insufficient. This review summarizes current evidence on ctDNA-based genotyping in mCRPC, highlighting clinically actionable mutations, corresponding targeted therapies, and technical and analytical considerations for clinical implementation. By capturing DNA shed from multiple metastatic sites, ctDNA profiling provides a comprehensive view of tumor heterogeneity and enables serial monitoring of molecular evolution. Overall, ctDNA analysis represents a transformative advance in precision oncology, supporting personalized treatment selection and ongoing assessment of therapeutic response in mCRPC. Full article

Ferroptosis is an iron-dependent form of regulated cell death driven by lipid peroxidation. Since the identification of dihydroorotate dehydrogenase (DHODH) as a mitochondrial suppressor of ferroptosis in 2021, increasing evidence has highlighted its role in linking nucleotide metabolism, redox regulation, and tumor progression. We conducted a comprehensive review of publications on DHODH, ferroptosis, and cancer. Relevant studies were analyzed to synthesize mechanistic insights, translational implications, and therapeutic perspectives. DHODH, a flavin-dependent mitochondrial enzyme catalyzing the oxidation of dihydroorotate to orotate, integrates pyrimidine biosynthesis with electron transport chain activity. Beyond its canonical metabolic role, DHODH regenerates ubiquinol (CoQ₁₀H₂) to suppress mitochondrial lipid peroxidation and ferroptosis. Elevated DHODH expression in colorectal, hepatocellular, breast, renal, and brain cancers correlates with poor prognosis, therapy resistance, and immune evasion. Pharmacological inhibition of DHODH disrupts pyrimidine synthesis and redox defense, sensitizing GPX4-low tumors to ferroptosis. Preclinical studies demonstrate synergy between DHODH inhibitors and chemotherapy, radiotherapy, or immune checkpoint blockade. Nanoparticle-based delivery systems enhance therapeutic efficacy by simultaneously targeting multiple ferroptosis defense arms while reducing toxicity. DHODH serves as both a metabolic and redox checkpoint in cancer, linking ferroptosis suppression to proliferation and immune escape. Targeting DHODH offers a promising strategy to dismantle cancer resilience, particularly in combination with ferroptosis inducers and immunotherapies. Future research should focus on biomarker-guided stratification, nanomedicine platforms, and clinical translation of DHODH inhibitors. Full article

Background/Objectives: The therapeutic landscape of advanced or metastatic urothelial carcinoma (UC) has shifted from platinum chemotherapy to precision immuno-oncology. Immune checkpoint inhibitors (ICIs)—pembrolizumab, nivolumab, and avelumab—show efficacy across platinum-refractory, maintenance, and adjuvant settings, yet benefit is limited to subsets, underscoring the need for biomarkers. Antibody–drug conjugates (ADCs), notably enfortumab vedotin(EV), and targeted agents such as FGFR inhibitors further expand options. This review synthesizes current evidence and emerging paradigms to guide combinations and sequencing. Methods: We performed a narrative synthesis of peer-reviewed trials (emphasizing pivotal phase III studies), key translational investigations, and contemporary guidelines on ICIs, ADCs, HER2-directed therapies, FGFR inhibitors, molecular subtyping, and genomic profiling in UC, integrating efficacy signals, biomarker associations, and practical implications for sequencing. Results: ICIs now occupy multiple settings, but heterogeneous benefit highlights the importance of molecularly informed selection. EV alone and with pembrolizumab has produced unprecedented first-line activity, prompting a strategic shift. Molecular subtyping and genomic profiling delineate phenotypes with variable immune responsiveness and targetable vulnerabilities, enabling rational combinations and refined sequencing. Ongoing trials are evaluating next-generation ADCs, HER2-directed approaches, and dual checkpoint blockade to achieve durable, personalized disease control. Conclusions: Management of locally advanced or metastatic UC is converging on precision immuno-oncology, wherein biomarker-driven selection, molecular subtyping, and thoughtful sequencing of ICIs, ADCs, and targeted agents are central to optimizing outcomes. Active trials and translational advances are expected to refine personalized strategies and embed molecular guidance into routine care. Full article

Background/Objectives: T cell dysfunction represents a fundamental barrier to effective cancer immunotherapy. Although immune checkpoint blockades and adoptive cell transfer have achieved clinical success, therapeutic resistance remains prevalent across cancer types. Thymopentin (TP5), a synthetic immunomodulatory pentapeptide (Arg-Lys-Asp-Val-Tyr), has demonstrated immunostimulatory properties, yet its anticancer potential remains unexplored. The aim of this study was to investigate TP5’s antitumor efficacy and underlying immunological mechanisms. Methods: We evaluated TP5’s therapeutic effects in multiple murine tumor models, including B16-F10 melanoma, MC38 colorectal carcinoma, Hepa 1-6, and LM3 hepatocellular carcinoma. Immune cell populations and functional states were characterized using flow cytometry, ELISAs, and immunofluorescence analyses. The potential of TP5 as an adjuvant for T cell-based therapies was also systematically assessed. Results: The TP5 treatment markedly suppressed tumor growth across caner models through strictly T cell-dependent mechanisms. Critically, TP5 promoted thymic rejuvenation under immunocompromised conditions, restoring the thymus–tumor immunological balance and revitalizing peripheral T cell immunity. TP5 functionally reprogrammed T cell states, preserving effector function while ameliorating exhaustion. Furthermore, TP5 demonstrated synergistic efficacy when combined with adoptive T cell therapies, enhancing both proliferation and effector functions. Conclusions: TP5 represents a promising immunomodulator that addresses fundamental limitations of current T cell therapies by simultaneously enhancing T cell function and reversing thymic involution under immunocompromised conditions. Our findings provide compelling evidence for TP5’s clinical translation in cancer treatment. Full article

Background: Most immunologically “cold” tumors do not respond durably to checkpoint blockade because tumor antigen (TA) release and presentation are insufficient to prime effective T-cell immunity. While prior work demonstrated synergy between cisplatin and a TLR7/8/9 agonist (CR108) in 4T1 tumors, the underlying mechanism—particularly whether chemotherapy functions as a broad antigen-releasing agent enabling TLR-driven immune amplification—remained undefined. Methods: Using murine models of breast (4T1), melanoma (B16-F10), and colorectal cancer (CT26), we tested multiple chemotherapeutic classes combined with CR108. We quantified intratumoral and systemic soluble TAs, antigen presentation and cross-priming by antigen-presenting cells, tumor-infiltrating lymphocytes, and cytokine production by flow cytometry/ICS. T-cell receptor β (TCRβ) repertoire dynamics in tumor-draining lymph nodes were profiled to assess amplitude and breadth. Tumor microenvironment remodeling was analyzed, and public datasets (e.g., TCGA basal-like breast cancer) were interrogated for expression of genes linked to TA generation/processing and peptide loading. Results: Using cisplatin + CR108 in 4T1 as a benchmark, we demonstrate that diverse chemotherapies—especially platinum agents—broadly increase the repertoire of soluble tumor antigens available for immune recognition. Across regimens, chemotherapy combined with CR108 increased T-cell recognition of candidate TAs and enhanced IFN-γ⁺ CD8⁺ responses, with platinum agents producing the largest expansions in soluble TAs. TCRβ sequencing revealed increased clonal amplitude without loss of repertoire breadth, indicating focused yet diverse antitumor T-cell expansion. Notably, therapeutic efficacy was not predicted by canonical damage-associated molecular pattern (DAMP) signatures but instead correlated with antigen availability and processing capacity. In human basal-like breast cancer, higher expression of genes involved in TA generation and antigen processing/presentation correlated with improved survival. Conclusions: Our findings establish an antigen-centric mechanism underlying chemo–TLR agonist synergy: chemotherapy liberates a broadened repertoire of tumor antigens, which CR108 then leverages via innate immune activation to drive potent, T-cell-mediated antitumor immunity. This framework for rational selection of chemotherapy partners for TLR7/8/9 agonism and support clinical evaluation to convert “cold” tumors into immunologically responsive disease. Full article

Peritoneal carcinomatosis (PC) is a late-stage manifestation of abdominopelvic malignancies with poor prognosis and limited treatment options. Unique biochemical mechanisms within the peritoneal cavity play a key role in disease progression and resistance to therapy. Despite current therapies like systemic chemotherapy and cytoreductive surgery, patients frequently develop severe complications, including bowel obstruction, nutritional decline, and ascites, driving the need to address the pro-tumorigenic niche in the peritoneal cavity. The immune microenvironment in PC is marked by elevated proinflammatory mediators, such as IL-6 and IL-8, which skew the response toward innate rather than adaptive immune responses. IL-8 signaling, through its receptors CXCR1 and CXCR2, promotes neutrophil recruitment, chronic inflammation, angiogenesis, epithelial–mesenchymal transition, and immune evasion, making the IL-8/CXCR1/CXCR2 axis a potential therapeutic target in PC. Pre-clinical models provide evidence that IL-8 or CXCR1/CXCR2 blockade may be a valuable therapeutic strategy. IL-8 targeting agents such as monoclonal antibodies (BMS-986253) and small-molecule inhibitors (SX-682, AZD5069, navarixin) have shown efficacy in mitigating tumor growth and improving the efficacy of immune checkpoint inhibitors. Phase I and II trials have demonstrated encouraging safety profiles and preliminary efficacy when treating multiple abdominopelvic malignancies. In this review, we discuss the influence of the IL-8/CXCR1/CXCR2 axis within the peritoneal immune environment in PC and highlight recent work using IL-8 or CXCR1/CXCR2 blockade as a therapeutic strategy for PC. Continued research into the peritoneal immune microenvironment and the development of targeted therapies are essential for improving the management and prognosis of PC, potentially enhancing antitumor immunity and patient outcomes. Full article

Proteasome subunit beta type-9 (PSMB9), a member of the proteasome beta subunit family, encodes the pivotal β1i component of the immunoproteasome. PSMB9 plays a crucial role in antigen processing and presentation; however, its comprehensive role in orchestrating a tumor-immune landscape and regulating the anti-tumor immune responses remains unexplored. Here we investigated the context-dependent functions of PSMB9 by integrating multi-omics data from The Cancer Genome Atlas, Genotype-Tissue Expression database, Human Protein Atlas, Tumor Immunotherapy Gene Expression Resource, and multiple other databases. Moreover, we explored the predictive value of PSMB9 in multiple immunotherapy cohorts and investigated its functional relevance in CAR-T therapy using genome-scale CRISPR/Cas9 screening, gene knockout cell line in vitro, and clinical cohort validation. We found widespread dysregulation in PSMB9 across cancers, predominantly upregulated in most malignancies and associated with advanced pathological stages in specific contexts. PSMB9 was also broadly and negatively correlated with tumor stemness indices. Crucially, PSMB9 expression was robustly linked to anti-tumor immunity by being significantly correlated with immune-pathway activation (e.g., IFN response, cytokine signaling), immune regulatory and immune checkpoint gene expression, and enhanced infiltration of T cells across nearly all tumor types. Consequently, elevated PSMB9 predicted superior response to immune checkpoint inhibitors in multiple cohorts, showing comparable predictive power to established predictive signatures. Furthermore, CRISPR/Cas9 screening identified PSMB9 loss as a novel mechanism of resistance to CD19 CAR T cell therapy, with PSMB9-deficient tumor cells exhibiting a survival advantage under CAR-T pressure, supported by trends in clinical CAR-T outcomes. Our study uncovers PSMB9 as a previously unrecognized critical regulator of the tumor immune landscape in a pan-cancer scope, whose expression orchestrates key immune processes within the tumor microenvironment and serves as a potent biomarker for patient prognosis. Critically, we first established PSMB9 as a novel prognostic indicator for both checkpoint blockade and CAR-T cell therapies, highlighting its dual role as a crucial immune modulator and a promising biomarker for guiding T cell-based immunotherapy strategies across diverse human cancers. Full article