Cancer Immunology, Immunotherapy[JOURNAL]
Sun
200 papers
Pan-cancer single-cell and spatial transcriptomics analyses delineate response-associated heterogeneity and therapeutic targets of tumor-infiltrating B cells following immune checkpoint blockade.
Fang J, Liu H, Lei J … +2 more , Chen Y, Wang J
Cancer Immunol Immunother · 2026 Jun · PMID 42247075 · Publisher ↗
Tumor-infiltrating B cells (TIBs) are emerging as central regulators of anti-tumor immunity, but their biological functions, spatial niches, and cross talk with tumor-infiltrating lymphocytes vary widely across cancer ty...
Tumor-infiltrating B cells (TIBs) are emerging as central regulators of anti-tumor immunity, but their biological functions, spatial niches, and cross talk with tumor-infiltrating lymphocytes vary widely across cancer types, particularly with regard to cancer immunotherapies. Yet a pan-cancer atlas linking their transcriptional profile to the immune checkpoint blockade (ICB) response has been missing. Here, we presented the pan-cancer ICB response B cell atlas, constructed from 688 single-cell transcriptomes (24 cancer types, 241,645 cells). Twenty-four B cell subsets were identified, and their proportion dynamics and transcriptomic features across cancers were revealed. B cell subsets proportion-based NMF analyses identified 5 TIME subtypes in which TIME-Plasma and TIME-Memory showing repressed apoptosis, higher antigen presentation, and enrichment in responders were correlated with better survival in several cancers. Pseudo-time trajectories delineated two conserved differentiation pathways that branch at the memory B cell node and showed distinct correlations with B cell apoptosis and ICB response. Pan-cancer spatial deconvolution showed that several responder-derived B cell subsets including plasma cells, memory B cells, and activated B cells were more co-occurred compared to non-responder-derived B cell subsets. Utilizing pan-cancer TCGA datasets, the clinical heterogeneity of B cell subsets from distinct response groups was revealed. We constructed a pan-cancer ICB response Geneformer model and in silico perturbed all genes. Thirteen candidate genes, which were significantly correlated with the B cell ICB response state transition, were identified. Overall, our study illuminates the heterogeneity of TIBs and improves our understanding of cancer-specific B cell subsets within the context of tumor immunotherapies.
Enhanced PD-L1 targeting boosts the cytotoxic activity of FOLR1- CAR NK92 cells against ovarian cancer.
Chen X, Huang J, Diao G … +6 more , Tian M, Yang Y, Liu D, Ma Y, Han J, Guo J
Cancer Immunol Immunother · 2026 Jun · PMID 42247058 · Publisher ↗
Chimeric antigen receptor (CAR)-T cells have achieved remarkable success against hematologic malignancies; however, their application is associated with risks such as cytokine release syndrome (CRS) and neurotoxicity. In...
Chimeric antigen receptor (CAR)-T cells have achieved remarkable success against hematologic malignancies; however, their application is associated with risks such as cytokine release syndrome (CRS) and neurotoxicity. In contrast, CAR-NK cells not only avoid these toxicities but also retain the natural cytotoxic activity of NK cells, demonstrating great potential for cancer immunotherapy.Our previous study demonstrated the potent efficacy of folate receptor alpha (FOLR1)-targeted CAR-NK92 cells against ovarian cancer (OC). Nevertheless, the application of CAR-NK therapy in solid tumors, including OC, still faces challenges such as tumor antigen heterogeneity and the immunosuppressive tumor microenvironment (ITME). A key mediator of ITME is programmed death-ligand 1 (PD-L1), which not only correlates with poor prognosis in OC but also drives T cell exhaustion via the PD-1/PD-L1 axis. Moreover, its inducible upregulation under NK cell-based therapy supports PD-L1 as a viable therapeutic target in OC.To enhance the therapeutic potential of CAR technology for OC, we engineered two novel third-generation bispecific CAR-NK92 cells based on our prior FOLR1-CAR design. These constructs-Tandem PD-L1/FOLR1-CAR (Tan-CAR1) NK92 and Tandem FOLR1/PD-L1-CAR (Tan-CAR2) NK92-were designed to simultaneously target FOLR1 and PD-L1. Notably, we confirmed that PD-L1 expression was significantly upregulated in the co-culture supernatant of effector and target cells. In vitro, Tan-CAR2 NK92 cells exhibited markedly superior cytotoxicity against FOLR1PD-L1 OC cells and enhanced degranulation compared with FOLR1-CAR NK92 cells. In xenograft mouse models, Tan-CAR2 NK92 cells showed effective tumor infiltration and induced significantly greater tumor regression than both FOLR1-CAR NK92 and PD-L1-CAR NK92 groups. In conclusion, the tandem bispecific CAR-NK92 cells developed in this study represent a meaningful advance in immunotherapy. Their dual mechanism-broader antigen recognition and enhanced immune infiltration-effectively addresses two major therapeutic barriers in OC, offering a promising strategy for treating refractory cases.
Integrated immunophenotypic and ProMisE molecular profiling as predictors of immune checkpoint inhibitor response in recurrent endometrial cancer.
Katayama K, Yoshikawa N, Liu W … +17 more , Nakamura K, Hattori S, Kubokawa M, Iyoshi S, Yoshida K, Yoshihara M, Nagao Y, Tamauchi S, Yokoi A, Niimi K, Shimizu Y, Kawai Y, Utsumi F, Watanabe E, Suzuki S, Shibata K, Kajiyama H
Cancer Immunol Immunother · 2026 Jun · PMID 42228031 · Publisher ↗
BACKGROUND: Immune checkpoint inhibitors (ICIs) are an important treatment option for recurrent endometrial cancer (EC); however, responses vary widely. Although the ProMisE molecular classification provides prognostic a...
BACKGROUND: Immune checkpoint inhibitors (ICIs) are an important treatment option for recurrent endometrial cancer (EC); however, responses vary widely. Although the ProMisE molecular classification provides prognostic and predictive insights, it does not fully explain the heterogeneity of ICI outcomes. Further characterization of the tumor immune microenvironment (TIME) is required to refine biomarker development. METHODS: We retrospectively analyzed 72 patients with recurrent EC treated with ICIs. Immune markers, including CD8, CD68, CD163, CD47, CD276, PD-L1, and HLA class I, were quantified using digital pathology. Associations between immune markers, ICI response, and progression-free survival (PFS) were evaluated overall and within ProMisE molecular subtypes. In an exploratory supplementary analysis, Foxp3 immunostaining was performed in 51 cases with additional FFPE material available. RESULTS: Responders exhibited a more immunologically active TIME, characterized by increased CD8⁺ T-cell infiltration in the central tumor (CT), whereas non-responders showed enriched CD68⁺ tumor-associated macrophages at the invasive margin (IM) and higher CD47 expression. Distinct immune landscapes were observed across ProMisE subtypes. Mismatch repair-deficient (MMRd) tumors demonstrated higher intratumoral CD8+ infiltration, whereas p53-abnormal (p53abn) tumors showed a more immunosuppressive profile, including elevated CD163+ macrophage density and CD47 expression. Subtype-specific analyses revealed that PFS was associated with different immune determinants, including CD8+ T cell infiltration in MMRd, CD47 expression level in no specific molecular profile (NSMP), and CD68.IM in p53abn. In the Forkhead box P3 (Foxp3) subset, the CD8/Foxp3 ratio showed a stronger association with ICI response and PFS than Foxp3 alone. CONCLUSIONS: Tumor immune phenotypes provide clinically relevant information complementary to ProMisE classification. Rather than indicating a single universal determinant, our results support a model in which cytotoxic T-cell infiltration and immunosuppressive pathways jointly shape ICI outcome in recurrent EC. Integrating ProMisE classification with immunological profiling may improve patient stratification of ICI benefits.
Preclinical evaluation of rBCG-h12: an engineered Bacillus Calmette-Guérin with an enhanced activity against bladder and pancreatic cancers.
Yeh CC, Fan CS, Chen LL … +13 more , Chua KV, Hsu CH, Chen CC, Tan ZL, Tsai PC, Song YD, Low YS, Yang SJ, Chen YY, Lin YX, Wu CM, Dou HY, Huang TS
Cancer Immunol Immunother · 2026 Jun · PMID 42223672 · Publisher ↗
BACKGROUND: Intravesical Bacillus Calmette-Guérin (BCG) therapy has been the standard treatment for preventing recurrence of non-muscle-invasive bladder cancer (NMIBC) for over four decades. Although maintenance BCG ther...
BACKGROUND: Intravesical Bacillus Calmette-Guérin (BCG) therapy has been the standard treatment for preventing recurrence of non-muscle-invasive bladder cancer (NMIBC) for over four decades. Although maintenance BCG therapy improves recurrence-free survival in intermediate- and high-risk NMIBC patients, its long treatment duration, toxicity, and limited efficacy - particularly in carcinoma in situ -necessitate the development of improved therapeutic alternatives. rBCG-h12 is a recombinant BCG strain engineered to enhance immunogenicity. This study evaluated its ability to augment macrophage activation and antitumor responses. METHODS: The safety of intravesical rBCG-h12 was evaluated in NOD/SCID and C57BL/6 mice through four weekly instillations. Body weight, survival, urine hematuria, and organ histopathology were monitored. Antitumor efficacy was tested using an orthotopic NMIBC transplant model. Immune microenvironment changes were analyzed by detecting macrophage and T cell markers. The systemic antitumor potential of rBCG-h12 was further evaluated via intramuscular injection in pancreatic cancer transplant and K-Ras mouse models. RESULTS: Intravesical rBCG-h12 was well tolerated, with no observed mortality, weight loss, hematuria, or organ pathology. Compared with conventional BCG, rBCG-h12 more effectively suppressed bladder tumor growth, prolonged survival, and mitigated cachexia. Mechanistically, rBCG-h12 decreased CD206 M2-macrophages while increasing CD4TNF-α effector T cells and CD8TNF-α cytotoxic T cells. In pancreatic cancer models, a single intramuscular injection of rBCG-h12 markedly reduced desmoplasia, suppressed tumor growth, and extended survival without inducing pathological lesion or granuloma formation in liver, lungs, and spleen. CONCLUSIONS: rBCG-h12 exhibited superior antitumor efficacy and safety compared with BCG. By suppressing M2-macrophages and promoting Th1 immune activation, rBCG-h12 shows promise as a next-generation BCG-based immunotherapy for both bladder and pancreatic cancers.
A novel oncolytic herpes simplex virus type 2 induces polarization of tumor-associated macrophages and remodels the immune microenvironment in glioblastoma.
Yang X, Li S, Lan Y … +12 more , Wang C, Zhang M, Zhao W, Zhang R, Huang M, Kang Z, Zhang B, Gu X, Chen F, Wu Z, Liu B, Li W
Cancer Immunol Immunother · 2026 May · PMID 42217049 · Publisher ↗
BACKGROUND: Glioblastoma multiforme (GBM) is a highly aggressive primary malignant brain tumor with limited survival despite multimodal therapy. Its profoundly immunosuppressive tumor microenvironment severely restricts...
BACKGROUND: Glioblastoma multiforme (GBM) is a highly aggressive primary malignant brain tumor with limited survival despite multimodal therapy. Its profoundly immunosuppressive tumor microenvironment severely restricts treatment efficacy. Oncolytic viruses represent a promising therapeutic strategy, yet the immunological mechanisms underlying the antitumor activity of OH2 (oncolytic herpes simplex virus type 2) remain poorly defined. METHODS: The effects of OH2 were evaluated in GBM cell lines (U251, LN229 and GL261) by assessing cell viability, migration, apoptosis, and cell cycle distribution. Modulation of tumor-associated macrophages (TAMs) was examined in RAW264.7 and THP-1 cells through functional assays, RNA sequencing, Western blotting and pharmacologic inhibition. In vivo studies were performed in subcutaneous and orthotopic GBM models to assess tumor growth and immune alterations. Exploratory clinical observations were conducted in seven recurrent GBM patients (NCT05235074), including peripheral blood monocyte profiling, longitudinal immune monitoring and cytokine analysis. RESULTS: OH2 induced apoptotic and oncolytic cell death in GBM cells, while inhibiting cell proliferation and migration in vitro. In macrophage models, exposure to OH2-conditioned media enhanced proliferation and phagocytic activity and promoted M1-like polarization, accompanied by activation of JAK-STAT1 signaling. In vivo, OH2 suppressed tumor growth, promoted M1-like TAM polarization, reduced immunosuppressive macrophage populations, and increased recruitment of bone marrow-derived macrophages into the brain. Exploratory clinical observation suggested that changes in peripheral monocyte profiles may be associated with clinical benefit. CONCLUSIONS: OH2 exerts antitumor activity in GBM through direct oncolysis and immune microenvironment modulation, highlighting its potential as an immunotherapeutic strategy.
Spatial transcriptomics of cervical cancer reveals microenvironment shaped the malignant epithelial programs and ECM-associated immune niches.
Chen Q, Lyu J, Li Y … +6 more , Zhang L, Zhao P, Gao G, Wang Y, Li C, Zhang X
Cancer Immunol Immunother · 2026 May · PMID 42215810 · Publisher ↗
OBJECTIVES: Cervical cancer progression and therapeutic response are influenced by intratumoral heterogeneity and the tumor microenvironment. The diversity of malignant epithelial subtypes and their interactions with imm...
OBJECTIVES: Cervical cancer progression and therapeutic response are influenced by intratumoral heterogeneity and the tumor microenvironment. The diversity of malignant epithelial subtypes and their interactions with immune cells present significant challenges for effective clinical management. METHODS: We applied Stereo-seq spatial transcriptomics to FFPE cervical cancer specimens to define malignant epithelial subpopulations via marker expression, functional enrichment, pseudotime trajectory inference, and transcription factor activity. Findings were validated using immunohistochemistry in CIN III and invasive carcinoma and public scRNA-seq dataset. Cell-cell communication and niche-specific ligand were performed using CellChat and NicheNet. RESULTS: Four malignant epithelial programs were identified, including a proliferative ITGB6⁺ Epi, an invasive-edge ITGA6⁺ Epi enriched for EMT and matrix adhesion, a stress-adaptive NDRG1⁺/PVT1⁺ Epi at the tumor-stroma interface, and a differentiated TMPRSS11D⁺ Epi with barrier-like features. Pseudotime analysis revealed a unidirectional trajectory from ITGB6⁺ progenitor-like cells, diverging toward either ITGA6⁺ or NDRG1⁺ states, converging on TMPRSS11D⁺ differentiation. IHC confirmed stage-associated expression patterns, including ITGB6 upregulated in invasive carcinoma and ITGA6 enriched at invasive fronts. Comparable epithelial heterogeneity was observed in scRNA-seq data. Communication analyses showed broad mesenchymal-epithelial interactions dominated by extracellular matrix ligands, ITGA6⁺ epithelium displaying a distinct matrix-oriented communication signaling profile involving laminin-associated and TGFA-EGFR signaling. NicheNet further highlighted THBS1 as prominent microenvironmental signals predicted to regulate ITGA6-associated targets. CONCLUSIONS: Cervical cancer displays spatially organized epithelial heterogeneity shaped by distinct microenvironmental niches. The ITGA6⁺ epithelial program is closely linked to matrix interactions and THBS1-associated signaling, suggesting a role in invasion and immune modulation.
Pertussis toxin-induced lymphocytosis shifts the tumor microenvironment toward immune activation via CXCL9 signaling.
Cho JK, Lee K, Shin DY … +4 more , Do Thanh Nguyen T, Park W, Im SJ, Jeong HS
Cancer Immunol Immunother · 2026 May · PMID 42209867 · Publisher ↗
BACKGROUND: A decrease in peripheral lymphocyte count in cancer patients predicts poorer prognosis and can be a useful discriminator in response to anti-tumor immunotherapy. However, therapeutic interventions to induce l...
BACKGROUND: A decrease in peripheral lymphocyte count in cancer patients predicts poorer prognosis and can be a useful discriminator in response to anti-tumor immunotherapy. However, therapeutic interventions to induce lymphocytosis and improve the efficacy of anti-tumor immunotherapy have not been investigated. METHODS: In this study, we used pertussis toxin (PTX) to induce lymphocytosis; toxicity was minimal at controlled doses. Using an in vivo squamous cell carcinoma (SCC) model, the effects of PTX on anti-PD1 treatment efficacy were evaluated. To characterize the underlying changes associated with PTX pretreatment, we conducted immunohistochemistry, transcriptomic analysis, flow cytometry, and chemokine array analyses. RESULTS: PTX increased lymphocyte counts in SCC-tumor-bearing mice and shifted tumors from low to high immune scores. PTX-induced elevation of CXCL9 led to lymphocytosis and increased immune cell infiltration in tumor tissues. Combining PTX with an anti-PD1 antibody significantly suppressed in vivo SCC tumor growth compared with anti-PD1 treatment alone. The combination treatment induced a greater proportion of T cells in the tumor microenvironment, and these findings were associated with increased terminally differentiated CD8 T cells and higher Ki-67 expression. In addition, tumor-specific IFN-γ production was augmented in animals treated with anti-PD1 antibody and combination treatments, but not with PTX alone. CONCLUSIONS: PTX can induce high lymphocyte infiltration into the tumor microenvironment, creating a favorable immune environment for immune checkpoint inhibitors. These PTX actions could enhance the efficacy of anti-PD1 treatment in an in vivo SCC model.
Flow-cytometric profiling of large extracellular vesicles as immunophenotypic biomarkers in head and neck squamous cell carcinoma.
Büntzel J, Maulhardt M, Angleitner AC … +8 more , Schulz M, Köberle D, Naser S, Zwerenz C, Pagel CF, Hille A, Hund AC, Büntzel J
Cancer Immunol Immunother · 2026 May · PMID 42203995 · Full text
BACKGROUND: Large extracellular vesicles (large EV) released from tumor and benign cells are detectable in blood and hold potential as non-invasive biomarkers. While their diagnostic relevance has been shown in several m...
BACKGROUND: Large extracellular vesicles (large EV) released from tumor and benign cells are detectable in blood and hold potential as non-invasive biomarkers. While their diagnostic relevance has been shown in several malignancies, their role in head and neck squamous cell carcinoma (HNSCC) remains insufficiently characterized. METHODS: Large EV were isolated from peripheral blood of patients with HNSCC (n = 66), non-small cell lung cancer (NSCLC; n = 52; adenocarcinoma n = 39, squamous cell carcinoma (SQCCL) n = 11), and healthy controls (n = 11) by differential centrifugation. Flow cytometry quantified surface expression of EGFR, EPCAM, MUC1, and PD-L1. Associations with clinical parameters were analyzed using t-tests, Spearman correlations, logistic regression, and random forest modeling. RESULTS: HNSCC-derived large EV showed significantly higher EGFR and MUC1, but lower EPCAM expression compared to controls. PD-L1 expression increased with advancing tumor stage and was positively associated with metastatic status, whereas EGFR levels declined in metastatic disease. Combined ROC analysis of EGFR, EPCAM, and PD-L1 yielded an AUC of 0.785 (p = 0.003), distinguishing HNSCC from controls. Comparative profiling revealed higher EGFR and EPCAM expression in HNSCC versus NSCLC, while MUC1 predominated in NSCLC, particularly in SQCCL; notably, the NSCLC cohort was predominantly adenocarcinoma. A marker panel comprising EGFR, EPCAM, and MUC1 differentiated HNSCC from SQCCL in this limited subgroup (n = 11) with 96.97% sensitivity, 45.45% specificity, 92.75% positive predictive value and 75.00% negative predictive value. CONCLUSION: Flow-cytometric profiling of circulating large EV provides a feasible liquid biopsy approach for tumor characterization in HNSCC. PD-L1 expression reflects tumor burden, and combined large EV marker analysis enables differentiation between HNSCC and primary squamous lung carcinoma, supporting its diagnostic utility in clinical oncology.
Enterotype-specific microbial biomarkers of immune checkpoint inhibitor response revealed by large-scale integrated metagenomic analysis.
Candeliere F, Busi E, Cerri S … +13 more , Sola L, Lombardi M, Greco S, Pedroni S, Amaretti A, Raimondi S, Chiavelli C, Vitale MG, Bertolini F, Depenni R, Franchini G, Dominici M, Rossi M
Cancer Immunol Immunother · 2026 May · PMID 42189287 · Publisher ↗
The gut microbiota appears to play a critical role in modulating antitumor immune responses and influencing the efficacy of cancer immunotherapy drugs such as immune checkpoint inhibitors. However, the identification of...
The gut microbiota appears to play a critical role in modulating antitumor immune responses and influencing the efficacy of cancer immunotherapy drugs such as immune checkpoint inhibitors. However, the identification of consistent microbial biomarkers of response remains a significant challenge. This lack of consensus is largely driven by multi-source heterogeneity, including geographic variations in lifestyle, and high inter-individual variability. We hypothesize that these inconsistencies arise because microbiome composition is not uniform but organized into distinct enterotypes. To address this, we performed an integrated metagenomic analysis of 569 fecal samples from oncological patients affected by different tumor types treated with immunotherapy. The samples were clustered into two main enterotypes, E1 and E2, each of them containing two subclusters. A total of 166 species (e.g., Collinsella spp., Blautia spp., Bacteroides spp.) were identified as enterotype-specific biomarkers. A preliminary independent concordance assessment of these biomarkers was conducted in 19 oncologic patients with exceptional response to immunotherapy, providing an initial confirmation of selected enterotype-associated signals. Furthermore, we evaluated the predictive potential of gut microbiota profiles for immunotherapy outcomes through machine learning techniques. The models showed encouraging, albeit moderate, performance in the heterogeneous full dataset, supporting the potential of microbiome-based stratification as an exploratory framework for patient classification, while indicating that further validation is needed before clinical application.
IAR025, a novel anti-DLL3 x CD3-bispecific antibody, displays high antitumor efficacy in preclinical models of small-cell lung cancer.
Liu Y, Cao L, Xu M … +10 more , Li N, Zhang J, Zhu M, Kuang Z, Sha H, Wu M, Xu J, Wu Z, Feng Y, Li L
Cancer Immunol Immunother · 2026 May · PMID 42189233 · Publisher ↗
Small-cell lung cancer (SCLC) is one of the most aggressive subtype of lung carcinoma with limited treatment options. Delta-like ligand 3 (DLL3), a Notch ligand protein, has been an attractive target for SCLC due to its...
Small-cell lung cancer (SCLC) is one of the most aggressive subtype of lung carcinoma with limited treatment options. Delta-like ligand 3 (DLL3), a Notch ligand protein, has been an attractive target for SCLC due to its high expression on SCLC but limited expression on normal tissues. Here, we developed a bispecific T cell engager, IAR025, and investigated its antitumor efficacy against SCLC. IAR025 has a CD3 arm for T cell activation and a DLL3 arm for recognizing tumor cells with optimal affinity and binding domain. IAR025 resulted in a dose-dependent eradication of DLL3-positive SCLC cells, without nonspecific cell destruction in DLL3-negative cells in vitro. Administration of IAR025 in DMS79 and SHP-77 humanized mouse models significantly inhibited tumor growth. The mechanism study revealed that IAR025 treatment led to increased T-cell recruitment in tumors. IAR025 activity was further enhanced when combined with chemotherapy or anti-PD-1 treatment. In cynomolgus monkeys, IAR025 was well-tolerated at a dose up to 10 mg/kg and exhibited linear pharmacokinetics with a half-life of 90 h. Collectively, these preclinical results demonstrate that IAR025 is a highly potent therapeutic strategy for treating SCLC.
Role of the Wnt5A pathway in resistance to immune checkpoint inhibitors in advanced Non-Small Cell Lung Cancer.
Takam Kamga P, Costantini A, Capron C … +4 more , Glorion M, Julie C, Emile JF, Giroux-Leprieur É
Cancer Immunol Immunother · 2026 May · PMID 42178414 · Publisher ↗
BACKGROUND: β-catenin-independent Wnt signaling plays a role in lung carcinogenesis, but its impact on prognosis and immune response in Non-Small Cell Lung Cancer (NSCLC) patients receiving immune checkpoint inhibitors (...
BACKGROUND: β-catenin-independent Wnt signaling plays a role in lung carcinogenesis, but its impact on prognosis and immune response in Non-Small Cell Lung Cancer (NSCLC) patients receiving immune checkpoint inhibitors (ICI) remains unclear. This study evaluates the prognostic significance of Wnt5a and Wnt5b and their role in immune modulation. METHODS: A prospective cohort of 52 consecutive advanced NSCLC patients receiving first-line ICI therapy was analyzed. Plasma samples were analysed using ELISA to quantify Wnt5a/Wnt5b. PBMCs were stimulated with PHA ± Pembrolizumab and co-cultured with recombinant Wnt5a or NSCLC explants. Wnt signaling inhibition was achieved using porcupine inhibitors (IWP-2/IWP-4) or neutralizing Wnt5a antibody. CD8 + T cell activation and cytokine production (INFγ, IL-6, IL-10) were measured by flow cytometry and ELISA. RESULTS: We observed that Wnt5a levels were significantly elevated in NSCLC patients and correlated with poor tumor response (RR = 2.4, p = 0.05) and shorter progression-free survival (Hazard Ratio (HR) = 2.77; 95% CI 1.11-6.88; p = 0.028.). In vitro, Wnt5a suppressed CD8 + T cell activation and INFγ production. These immunosuppressive effects were reversed by Wnt5a inhibitors, highlighting their potential as therapeutic agents to improve immune response in NSCLC patients receiving ICI therapy. CONCLUSIONS: Overall, high Wnt5a correlates with immune suppression and poor ICI response, suggesting its potential as a predictive biomarker and therapeutic target in NSCLC.
Real-world efficacy and safety of immune checkpoint blockades in advanced urothelial carcinoma with histologic variant subtypes: the pembroblad study.
Amrane K, Campedel L, Moinard-Butot F … +19 more , Gout M, Mahammedi H, Bennamoun M, Herrmann T, Gabriel PE, Pouessel D, Roulleaux-Dugage M, Thibault C, Cancel M, Flechon A, Huillard O, Abbar B, Borchiellini D, Doublet L, Augusto-Pelegrin L, Boughalem E, Cornillon P, Dumont C, Barthélémy P
Cancer Immunol Immunother · 2026 May · PMID 42177701 · Publisher ↗
BACKGROUND: Histologic variants (HV) of urothelial carcinoma (UC-V) and non-urothelial carcinomas (NUC) of the bladder and urinary tract are aggressive malignancies with poor prognosis and limited response to platinum-ba...
BACKGROUND: Histologic variants (HV) of urothelial carcinoma (UC-V) and non-urothelial carcinomas (NUC) of the bladder and urinary tract are aggressive malignancies with poor prognosis and limited response to platinum-based chemotherapy. Despite their biological particularities and distinct immune microenvironments, these HV subtypes are under-represented in immune checkpoint blockade (ICB) trials. METHODS: PEMBROBLAD is a French national multicenter retrospective study conducted across 24 centers. We included patients with advanced UC-V or NUC who received second-line anti-PD-(L)1 monotherapy after progression on platinum-based chemotherapy between 2016 and 2022. Primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. RESULTS: We included 129 UC-V and 34 NUC. With a median follow-up was 21.9 months, the median OS was 8.6 [95% confidence interval (CI), 5.3-11.2] months, with 8.5 [95% CI 5.3-10.9] months for UC-V and 10.5[95% CI 3.5-22.8] months for NUC. The median PFS was 2.6 [95% CI 2.1-3.4] months with 2.5 [95% CI 2.0-3.4] months for the UC-V group and 2.6 [2.0-3.4] months for the NUC group. ORR was 31.4% overall (complete response 15.3%, partial response 16.1%). In multivariable analysis, ECOG performance status ≥ 2 was independently associated with both poorer OS (HR 3.30, 95% CI 1.22-8.92; p = 0.018) and PFS (HR 2.32, 95% CI 1.52-3.54; p < 0.001). Pembrolizumab treatment was associated with improved PFS (HR 0.53, 95% CI 0.31-0.81; p = 0.017). Grade ≥ 3 immune-related adverse events occurred in 10.8% of patients, with no treatment-related deaths. CONCLUSIONS: Anti-PD-(L)1 monotherapy shows clinical benefit in advanced UC-V and NUC after platinum failure.
GFI1 enhances MHC-I expression in tumor cells and augments tumor responsiveness to PD-1/PD-L1 inhibitors.
Xi Y, Xiao K, Meng K … +8 more , Yu T, Wang T, Wang X, Pan O, Zeng C, Wang X, Fu X, Li L
Cancer Immunol Immunother · 2026 May · PMID 42174278 · Publisher ↗
BACKGROUND: Growth factor-independent-1 transcription repressor (GFI1) is crucial for determining the differentiation and fate of exhausted CD8 T cells and affects immunotherapy outcomes. However, the effects of tumor ce...
BACKGROUND: Growth factor-independent-1 transcription repressor (GFI1) is crucial for determining the differentiation and fate of exhausted CD8 T cells and affects immunotherapy outcomes. However, the effects of tumor cell-intrinsic GFI1 on antitumor immunity and the response to immunotherapy remain unknown. METHODS: The tumor cell-intrinsic expression of GFI1 was examined via RT‒qPCR and Western blotting. Immunohistochemical staining of tumor tissues was performed to assess the relationships among GFI1, CD8, and MHC I expression. A syngeneic mouse model and clinical tumor samples from NSCLC patients undergoing immunochemotherapy were used to evaluate how tumor cell-intrinsic GFI1 affects the response to immunotherapy. Additionally, techniques such as flow cytometry, immunoprecipitation, ChIP-qPCR, immunofluorescence, and both loss- and gain-of-function approaches were employed to investigate the underlying mechanisms involved. RESULTS: Tumor-intrinsic GFI1 expression was positively associated with MHC I expression and the infiltration of CD8 T cells. Tumors with higher GFI1 levels showed a significantly better response to immunotherapy. The overexpression of GFI1 in tumor cells increases MHC-I expression in a STAT1-dependent manner. Mechanistic analysis revealed that GFI1 inhibits HDAC1 activity in tumor cells by promoting its export to the cytoplasm, thereby increasing H3K9 acetylation and the transcription of STAT1 and MHC-I. Additionally, phenformin, an AMPK activator, increases GFI1 levels by downregulating EZH2 expression. Compared with anti-PD-L1 therapy alone, combining phenformin with anti-PD-L1 therapy enhances antitumor effects. CONCLUSIONS: This study demonstrated the crucial role of tumor-intrinsic GFI1 in enhancing antitumor immune responses, suggesting a new target for increasing the effectiveness of PD-1/PD-L1 blockade.
TGF-β inhibition enhances anti-tumor immunity and sensitizes PD-1 blockade therapy of bone marrow-derived myofibroblasts-induced "immunotherapy resistance" tumor model.
Cheng X, He L, Zhou C … +5 more , Li Q, Zhang B, Wang J, Cheng X, Tu S
Cancer Immunol Immunother · 2026 May · PMID 42171771 · Publisher ↗
Resistance to immune checkpoint blockade (ICB) therapy in certain solid tumors remains a major research focus; yet, the underlying mechanisms are not fully understood. Our previous studies demonstrated that subcutaneous...
Resistance to immune checkpoint blockade (ICB) therapy in certain solid tumors remains a major research focus; yet, the underlying mechanisms are not fully understood. Our previous studies demonstrated that subcutaneous tumors formed by a mixture of bone marrow-derived myofibroblasts (BMFs) and tumor cells not only grew faster than those formed by tumor cells alone but were also resistant to ICB therapy. However, the specific mechanism by which BMFs mediate this immune resistance remained unclear. In this study, we established a "BMF + MC38" mixed-cell subcutaneous tumor model to further validate its ICB therapy-resistant phenotype, investigate the mechanism underlying BMF-mediated immune resistance, and explore potential therapeutic strategies for this "immune-excluded" type of tumor. Our findings revealed that "BMF + MC38" mixed-cell subcutaneous tumors lost sensitivity to anti-PD-1 antibody treatment. Furthermore, these mixed-cell subcutaneous tumors exhibited significantly impaired CD8+ T cell infiltration and function, along with an increased proportion of regulatory T cells (Tregs). Higher expression of TGFβ1 was detected in the mixed-cell tumors compared to the MC38 cell tumors. Importantly, either reducing BMF-derived TGFβ1 expression or concurrently targeting PD-1 and TGFβ effectively restored the sensitivity to PD-1 blockade, rescued CD8+ T cell infiltration and function. Additionally, this study revealed that simultaneously targeting PD-1, TGFβ, and VEGFR further suppressed the growth of these mixed-cell subcutaneous tumors. These findings provide a viable combination targeted therapy strategy for the clinical treatment of solid tumors that are insensitive to immunotherapy.
Overcoming resistance in CD44-overexpressing myeloma through combination therapy with ATRA, bortezomib, and NK cells.
Nguyen VT, Thi TN, Tran VD … +13 more , Vo MC, Chu TH, Jang HC, Kim M, Song GY, Ahn SY, Ahn JS, Yang DH, Kim HJ, Cho D, Lee C, Jung SH, Lee JJ
Cancer Immunol Immunother · 2026 May · PMID 42165861 · Publisher ↗
CD44 is a cell-surface glycoprotein frequently overexpressed in cancers and associated with poor prognosis. We evaluated the prognostic significance of CD44 overexpression in multiple myeloma (MM) and investigated the th...
CD44 is a cell-surface glycoprotein frequently overexpressed in cancers and associated with poor prognosis. We evaluated the prognostic significance of CD44 overexpression in multiple myeloma (MM) and investigated the therapeutic efficacy of combining natural killer (NK) cell therapy with all-trans retinoic acid (ATRA) and bortezomib (Bor) against CD44-overexpressing MM. Clinical data from the CoMMpass database were analyzed to assess survival outcomes relative to CD44 expression. NK cells were expanded from healthy donors using K562-OX40L-mbIL-18/21 feeder cells supplemented with interleukin (IL)-2 and IL-15. Functional assays were performed using CD44-high myeloma cell lines treated with ATRA and Bor, individually or in combination with NK cells. Therapeutic efficacy was evaluated based on tumor growth, systemic dissemination, and survival in an intravenous U266-green fluorescent protein-firefly luciferase xenograft NOD/SCID IL-2Rγnull mouse model. Clinical data showed CD44 overexpression correlated with inferior overall survival (P < 0.0001) in all three stages I, II, and III of the revised International Stage System. In vitro, ATRA and Bor co-treatment downregulated β-catenin and CD44 expression, inhibited proliferation, migration, and invasion, and enhanced NK cell-mediated cytotoxicity via upregulation of MICA/B, Fas, TRAIL-R2, and intercellular adhesion molecule-1. In vivo, combination therapy with NK cells, ATRA, and Bor significantly suppressed CD44 expression, reduced extramedullary spread, and prolonged survival without notable toxicity. These preclinical findings support CD44 overexpression as a marker associated with inferior survival in MM and provide a rationale for pharmacologic tumor priming with ATRA and bortezomib to enhance NK cell-mediated cytotoxicity. However, the therapeutic strategy requires further validation in heterogeneous patient-derived models and prospective clinical studies before clinical efficacy can be inferred.
β-hydroxybutyrate potentiates anti-tumor immunity by modulating cytotoxic CD8 T cell responses.
Bai Y, Xue H, Bao Y … +6 more , Pan Y, Tang J, Wang M, Wang Y, Xu J, Huang J
Cancer Immunol Immunother · 2026 May · PMID 42162440 · Publisher ↗
Ketogenic diets (KDs) have been reported to influence tumor progression through metabolic and immunological modulation of the tumor microenvironment. β-hydroxybutyrate (βOHB), the predominant ketone body elevated by KD,...
Ketogenic diets (KDs) have been reported to influence tumor progression through metabolic and immunological modulation of the tumor microenvironment. β-hydroxybutyrate (βOHB), the predominant ketone body elevated by KD, functions not only as an energy substrate but also as a potent signaling metabolite. Despite its role in modulating the tumor microenvironment, the direct impact of βOHB on the function of CD8 T cell, a key mediator of anti-tumor immunity, remains incompletely understood. Here, we demonstrate that βOHB suppresses tumor growth in multiple mouse tumor models by enhancing the accumulation, survival, and effector function of tumor-infiltrating CD8 T cells. In contrast, acetoacetate does not exert comparable immunomodulatory effects. Mechanistically, βOHB upregulates the Tcf7-Lck signaling pathway by engaging with the cell surface receptor Hcar2, an effect potentially working in parallel with its role as an HDAC inhibitor. Knockdown of either Tcf7 or Hcar2 in CD8 T cells abolishes the promoting effect of βOHB on CD8 T function. Our findings elucidate a metabolite-immune axis that directly regulates the functional state of tumor-infiltrating CD8⁺ T cells and provide experimental evidence linking ketone metabolism to anti-tumor immune regulation.
Cytokine-induced killer (CIK) Cells-associated transcriptome signature reveals the potential immunomodulatory role of TNFSF14 in clear cell renal cell carcinoma.
Chen Y, Chen L, Qin X … +7 more , Li Y, Wu D, Setiawan MF, Lukacs-Kornek V, Ritter M, Sharma A, Schmidt-Wolf IGH
Cancer Immunol Immunother · 2026 May · PMID 42159775 · Full text
Among adoptive immune cell therapies, cytokine-induced killer cell (CIK) therapy has demonstrated clear therapeutic relevance in multiple cancers, particularly clear cell renal cell carcinoma (ccRCC). Despite being clini...
Among adoptive immune cell therapies, cytokine-induced killer cell (CIK) therapy has demonstrated clear therapeutic relevance in multiple cancers, particularly clear cell renal cell carcinoma (ccRCC). Despite being clinically successful, the molecular signatures associated with the immune-regulatory role of these CIK cells in cancers remain elusive. Considering this, we systematically identified CIK expansion-induced genes (CIK-EIGs) from their transcriptome profiles and curated the CIK-EIG-anchored transcriptome framework across bulk and single-cell ccRCC datasets. Using comprehensive bioinformatics analysis, we next developed the CIK-EIG-anchored risk stratification (CIKRRS), which enabled reliable prediction of patient prognosis, correlated with the clinical-pathological course, and defined an immunologically inflamed but clinically unfavorable phenotype. Of interest, the integrative analyses highlighted TNFSF14 as one of the key functional modulators within the CIK-EIG-associated immune landscape, showing a strong association with cytotoxic immune signaling and cancer-immunity cycle activity. Subsequently, the functional assays verified that TNFSF14 significantly enhanced CIK-mediated tumor cell killing, degranulation, and cytokine production in ccRCC cell lines, confirming its role in enhancing CIK effector function. Taken together, our findings present a CIK-EIG-anchored transcriptomic and prognostic framework and highlight the potential relevance of TNFSF14 for further optimization of CIK-based immunotherapy in ccRCC patients.
Vorinostat unmasks MAEL to enhance DC vaccine-induced CTL killing in hepatocellular carcinoma, potentiated by TIGIT checkpoint inhibition.
Liu C, Zhang Q, Zhang J … +3 more , Liu W, Geng S, Zhang J
Cancer Immunol Immunother · 2026 May · PMID 42156581 · Publisher ↗
BACKGROUND: To address the limited immunogenicity and immune evasion in hepatocellular carcinoma (HCC), this study developed a combinatorial immunotherapy strategy combining antigen-specific vaccination, epigenetic modul...
BACKGROUND: To address the limited immunogenicity and immune evasion in hepatocellular carcinoma (HCC), this study developed a combinatorial immunotherapy strategy combining antigen-specific vaccination, epigenetic modulation, and TIGIT-targeted checkpoint blockade. METHODS: Bioinformatic screening identified the cancer-testis antigen MAEL as a target. HLA-A*02:01-restricted MAEL peptides were used to pulse monocyte-derived dendritic cells (DCs), which primed cytotoxic T lymphocytes (CTLs). The CTL cytotoxicity against HCC cells was tested. HCC cells were treated with the HDAC inhibitor vorinostat to enhance MAEL expression, and its impact on CTL killing was evaluated. The triple combination (MAEL specific CTLs + vorinostat + anti-TIGIT) was tested in HCC xenograft mouse models, with analyses of tumor growth, survival, and immune infiltration. RESULTS: MAEL was confirmed as an HCC-associated antigen with restricted normal tissue expression. MAEL peptide-pulsed DCs generated potent CTLs with cytotoxicity against HLA-A*02:01⁺ HCC lines. Vorinostat upregulated MAEL expression, enhancing CTL killing (p < 0.01). In vivo, the dual combination (MAEL specific CTLs + vorinostat) outperformed monotherapies, reducing tumor growth and prolonging survival. The triple combination achieved the strongest anti-tumor effects, with significant regression and extended survival, via increased activated MAEL specific CD8⁺ T cell infiltration and enhanced CTL effector functions (elevated IFN-γ, TNF-α). CONCLUSION: This triple combination strategy synergistically enhances HCC immunotherapy. Vorinostat induces MAEL expression to "unmask" tumors, while TIGIT blockade overcomes T cell exhaustion, amplifying antigen-specific CTL activity. This approach shows promise for HCC treatment.
Early increase of CD103 expression on peripheral PD-1 CD8 T cells predicts response to nivolumab in advanced esophageal squamous cell carcinoma.
Sumimoto S, Makino T, Nakai S … +10 more , Hagi T, Momose K, Yamashita K, Saito T, Tanaka K, Takahashi T, Kurokawa Y, Nakajima K, Eguchi H, Doki Y
Cancer Immunol Immunother · 2026 May · PMID 42154065 · Publisher ↗
BACKGROUND: Nivolumab has become a standard treatment for advanced or recurrent esophageal squamous cell carcinoma (ESCC). However, reliable blood-based biomarkers predictive of response remain undefined. We investigated...
BACKGROUND: Nivolumab has become a standard treatment for advanced or recurrent esophageal squamous cell carcinoma (ESCC). However, reliable blood-based biomarkers predictive of response remain undefined. We investigated dynamic changes in peripheral PD-1 CD8 T-cell subsets during nivolumab therapy and evaluated their clinical significance. PATIENTS AND METHODS: Fifty-seven patients with advanced or recurrent ESCC treated with nivolumab were enrolled in this retrospective observational study. Peripheral blood mononuclear cells were collected before treatment and at 1, 2, and 4 weeks after initiation. Flow cytometric analyses evaluated the expression of CD103, CD45RA, Tim-3, LAG-3, TIGIT, and Ki-67 among nivolumab-binding PD-1CD8 T cells. Associations between immunophenotypic changes, treatment response, survival outcomes, immune-related adverse events (irAEs), and nutritional/inflammatory indices were analyzed. RESULTS: The objective response rate was 24.6%, and the median overall survival (OS) was 11.7 months. CD103 expression among PD-1 CD8 T cells significantly increased after nivolumab initiation and was sustained up to 4 weeks. At 4 weeks, responders showed significantly higher CD103 frequency than non-responders (P = 0.00407). Patients with high CD103 expression demonstrated significantly improved OS (P = 0.0421), whereas progression-free survival was not significantly different. CD103 expression was not correlated with baseline nutritional or inflammatory markers. Responders more frequently experienced irAEs, particularly rash. CONCLUSIONS: Early elevation of CD103 expression among peripheral PD-1 CD8 T cells was associated with objective response and improved overall survival in patients with ESCC and may represent a minimally invasive exploratory biomarker during nivolumab therapy.
Decoding circulating neutrophil phenotypes in triple-negative breast cancer via optimized single-cell RNA sequencing.
Banacki M, Pastuszak K, Sieczyński M … +5 more , Suchodolska G, Senkus E, Inkielewicz-Stepniak I, Supernat A, Żaczek A
Cancer Immunol Immunother · 2026 May · PMID 42154046 · Publisher ↗
Neutrophils are emerging as key regulators of tumor biology, influencing cancer progression, immune evasion, and therapeutic response. However, their transcriptomic characterization remains challenging due to low RNA con...
Neutrophils are emerging as key regulators of tumor biology, influencing cancer progression, immune evasion, and therapeutic response. However, their transcriptomic characterization remains challenging due to low RNA content, limiting confident discrimination from other leukocyte populations at the single-cell level. To address this, we developed a robust analytical framework for single-cell RNA sequencing data, calculating a neutrophil score for each cell based on two curated neutrophil marker gene panels and excluding cells expressing non-neutrophil marker genes.White blood cells were isolated from liquid biopsies of six triple-negative breast cancer (TNBC) patients and six non-malignant donors, sequenced, and analyzed to profile 84 neutrophils isolated from TNBC patients and 128 neutrophils isolated from control donors. TNBC neutrophils displayed significant upregulation of migration-associated genes (-log adjusted p ≈ 3) and respiratory complex genes (p < 1 × 10) compared with controls.These findings demonstrate significant transcriptomic differences between the TNBC and control neutrophils, revealing a part of the influence of the TNBC tumor on circulating immune cells. Moreover, this work provides a validated framework for precise neutrophil identification and functional characterization in single-cell studies and lays the foundation for dissecting their mechanistic roles in cancer progression.
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