Liang R, Gao B, Nagrial A
… +9 more, Moujaber T, Carlino MS, Ding PN, Gurney H, Wong M, Habib R, Lo SN, McKeown J, da Silva IP
Cancer Immunol Immunother
· 2026 May · PMID 42118295
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BACKGROUND: Immune checkpoint inhibitors (ICIs) improve outcomes across advanced cancers but can cause immune-related adverse events (irAEs). Seasonal environmental factors influence immune regulation and autoimmunity, y...BACKGROUND: Immune checkpoint inhibitors (ICIs) improve outcomes across advanced cancers but can cause immune-related adverse events (irAEs). Seasonal environmental factors influence immune regulation and autoimmunity, yet its relationship with irAE development in non-melanoma cancers remains poorly defined. METHODS: We retrospectively analysed patients with advanced non-melanoma solid tumours treated with anti-PD-1/PD-L1 and/or anti-CTLA-4 monotherapy at two Australian tertiary centers between 2014-2024. Seasonal variation in irAE incidence, organ distribution, severity, and timing were evaluated using descriptive analyses, Kaplan-Meier estimates and Cox proportional hazards models. RESULTS: Among 709 patients across 27 cancer types (median follow-up 12.7 months), 514 irAEs occurred, including 32% grade ≥ 3 events and 14% treatment discontinuation rate due to toxicity. Winter ICI initiation led to the highest irAE rate (0.89 events per treatment) versus summer (0.62), largely driven by seasonal variation in low-grade cutaneous and thyroid events. Summer ICI initiation showed the highest proportion of grade ≥ 3 irAEs, whereas winter had the lowest. Seasonal effects also differed by regimen intensity, with disproportionately more irAEs among patients commencing doublet ICIs in winter. Season of ICI initiation was not significantly associated with overall irAE risk (p = 0.174) or time to onset (p = 0.11). However, time to first irAE differed by season of toxicity onset (p = 0.019), with earlier irAEs occurring in spring and summer. CONCLUSIONS: Although there was no significant association between season of ICI initiation and overall irAE risk, we observed seasonal variations in the phenotype, severity, and timing of irAEs. These exploratory findings may inform future investigation into seasonal influences on immune toxicity.
Nakai S, Makino T, Momose K
… +14 more, Yamashita K, Tanaka K, Miyata H, Yamamoto S, Motoori M, Kimura Y, Takeoka T, Hirao M, Matsuyama J, Akamaru Y, Kurokawa Y, Morii E, Eguchi H, Doki Y
Cancer Immunol Immunother
· 2026 May · PMID 42118259
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BACKGROUND: Programmed cell death protein-1 (PD-1) blockade improves survival in esophageal squamous cell carcinoma (ESCC), although only a subset of patients respond. We aimed to identify tumor-related biomarkers associ...BACKGROUND: Programmed cell death protein-1 (PD-1) blockade improves survival in esophageal squamous cell carcinoma (ESCC), although only a subset of patients respond. We aimed to identify tumor-related biomarkers associated with response and outcome in patients with unresectable or recurrent ESCC. METHODS: This multicenter retrospective study included 250 patients with unresectable or recurrent ESCC who received nivolumab as second- or later-line therapy. Pretreatment tumor specimens were evaluated by immunohistochemistry for p53, NY-ESO-1, MLH1, and programmed death-ligand 1 (PD-L1). PD-L1 expression was assessed using both tumor proportion score (TPS) and combined positive score (CPS) by using automated digital image analysis. Associations with objective response, progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: NY-ESO-1 expression was significantly associated with response to nivolumab (28.6% vs. 11.1%, P = 0.005) and remained independently associated with response in multivariate analysis (OR 3.32, 95% CI 1.49-7.28, P = 0.0027). PD-L1 expression was also associated with response according to both CPS and TPS. Patients with CPS ≥ 10% showed higher response rates than those with CPS < 10% (24.1% vs. 10.2%, P = 0.003), as well as longer median PFS (2.6 vs. 2.0 months, P = 0.0173) and OS (12.3 vs. 10.4 months, P = 0.0479). In contrast, p53 expression showed no significant association with response or survival, and MLH1 loss was rare. CONCLUSIONS: NY-ESO-1 expression was associated with response to nivolumab, while PD-L1 expression, particularly CPS, may provide clinically relevant prognostic information. Integrated assessment of tumor-related biomarkers and the host immune microenvironment may further improve patient stratification in ESCC.
Zhao L, Liu J, Zhang Y
… +6 more, Yang X, Chen T, Xu X, Zhou M, Hu Z, Guo Z
Cancer Immunol Immunother
· 2026 May · PMID 42113250
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Chimeric antigen receptor T-cell (CAR-T) therapy has achieved remarkable success in the treatment of hematological malignancies, and its application to solid tumors is currently under active investigation. Upon infusion...Chimeric antigen receptor T-cell (CAR-T) therapy has achieved remarkable success in the treatment of hematological malignancies, and its application to solid tumors is currently under active investigation. Upon infusion into the bloodstream, CAR-T cells are exposed to fluid shear stress (SS) generated by blood flow. However, the impacts of SS on CAR-T cells function are not well understood. In this study, we exposed anti-mesothelin (MSLN) CAR-T cells to a shear stress of 5 dynes/cm2, and observed reduced cell viability, enhanced activation, and decreased expression of exhaustion markers. Notably, we found that a one-hour SS stimulation applied seven days after T cell isolation and activation significantly increased the proportion of stem cell memory T cells (Tscm), mitigated exhaustion, and enhanced the anti-tumor efficacy of anti-MSLN CAR-T cells. Furthermore, SS-preconditioned CAR-T cells exhibited resistance to SS-induced cell death and demonstrated increased migratory capacity. In vivo experiments, SS-preconditioned CAR-T cells exhibited greater tumor infiltration, improved persistence, superior tumor control, and a favorable safety profile in tumor-bearing mice. Transcriptomic analysis revealed upregulation of genes associated with activation, infiltration, and microtubule dynamics, alongside downregulation of genes linked to exhaustion, apoptosis, and immunosuppression. Collectively, our findings demonstrate for the first time that mechanical preconditioning with fluid shear stress can reprogram CAR-T cells toward a more functional and persistent phenotype, offering a novel strategy to optimize CAR-T therapy for solid tumors.
Radovich M, Wacker J, Solzak J
… +13 more, Tae H, Ribeiro JR, Maney T, Hancock B, Hamrick J, Sledge GW, Ahluwalia MS, Liu SV, Lou E, Subbiah V, Halmos B, Magee D, Spetzler DB
Cancer Immunol Immunother
· 2026 May · PMID 42113041
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Although the tissue-agnostic FDA approval of pembrolizumab for tumor mutational burden (TMB)-high tumors has provided meaningful clinical benefit to patients, there remains a need to optimize TMB assessment. In this coho...Although the tissue-agnostic FDA approval of pembrolizumab for tumor mutational burden (TMB)-high tumors has provided meaningful clinical benefit to patients, there remains a need to optimize TMB assessment. In this cohort study, we investigated the discordance between whole-exome sequencing (WES) and panel-based methods and evaluated their relative clinical utility in identifying patients likely to benefit from pembrolizumab. Molecularly-profiled tumors from patients treated with pembrolizumab were analyzed (N = 26,756). TMB was calculated using WES data or panels of genes (324, 523, and 648) from commercially available assays (TMB-High ≥ 10 mutations/Mb). Pembrolizumab-specific overall survival (OS) was calculated from insurance claims data (treatment start to last contact). Targeted gene panels tended to overestimate TMB and demonstrated ~ 10-15% discordance in binary TMB calls from WES, which was most pronounced for the smallest panel. Discordant cases for all three panels clustered near the TMB clinical calling threshold. WES offered improved stratification of patients for pembrolizumab treatment: in a subset of "TMB-reliant" tumor types lacking disease-specific immune checkpoint inhibitor (ICI) indications (n = 3,981), median OS was approximately 5 months longer for cases identified as WES-TMB-High but panel-TMB-Low compared to those identified as WES-TMB-Low but panel-TMB-High (p < 0.05 for 324-gene and 648-gene panels). Approximately, 10-11% of patients were potentially misclassified by panels. These findings emphasize the importance of broader gene representation for accurate TMB determination near the clinical threshold-especially in tumor types lacking disease-specific ICI indications, where tissue-agnostic MSI-High/dMMR or TMB-High labeling represents the principal on-label route to ICI therapy.
Kuo HY, Huang TC, Chuang CH
… +6 more, Wu TC, Huang YL, Lin CC, Lee JM, Guo JC, Hsu CH
Cancer Immunol Immunother
· 2026 May · PMID 42105013
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PURPOSE: Anti-PD-1 immune-checkpoint inhibitors (ICIs) are approved for treating patients with recurrent or metastatic (R/M) esophageal squamous cell carcinoma (ESCC) who have failed platinum-based chemotherapy. However,...PURPOSE: Anti-PD-1 immune-checkpoint inhibitors (ICIs) are approved for treating patients with recurrent or metastatic (R/M) esophageal squamous cell carcinoma (ESCC) who have failed platinum-based chemotherapy. However, their efficacy as monotherapy remains limited. We hypothesized that adding cabozantinib, a multikinase inhibitor with antiangiogenic and immunomodulatory properties, could enhance the therapeutic efficacy of atezolizumab, an anti-PD-L1 ICI, in patients with R/M ESCC. PATIENTS AND METHODS: A single-arm, single-institution phase II trial was conducted (NCT05007613) that included patients with ESCC who experienced disease progression following a platinum-based chemotherapy for R/M ESCC or within 6 months after chemo(radio)therapy for locoregional disease. Participants received cabozantinib 40 mg daily and atezolizumab 1200 mg every 3 weeks until disease progression or intolerable toxicity was reached. The primary endpoint was investigator-assessed objective response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity profile. RESULTS: Between June 2021 and March 2024, 24 patients were enrolled in this study. With a median follow-up of 7.0 months (range, 0.5-38.1), 7 patients achieved partial responses and 7 had stable disease. The ORR was 29.1% (95% CI = 11.7%-60.1%), and the disease control rate (DCR) was 58.3% (95% CI = 31.9-97.9%). The median duration of response was 6.5 months (95% CI = 0.9-12.1), the median PFS was 2.2 months (95% CI = 0.64-3.76), and the median OS was 7 months (95% CI = 2.36-11.64). Of the 24 patients, 12 (50%) experienced ≥ grade 3 treatment-related adverse events. Patients with high PD-L1 expression and increased intratumoral or stromal CD8+ tumor infiltrating lymphocytes had numerically higher ORR and improved OS. CONCLUSION: The combination of cabozantinib and atezolizumab has an acceptable safety profile and moderate antitumor activity as a second-line treatment for patients with R/M ESCC.
Cancer Immunol Immunother
· 2026 May · PMID 42104144
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Immune checkpoint inhibitors (ICI), epitomized by PD-1/PD-L1 antibodies, have ushered in a new era in lung cancer treatment. However, ICI monotherapy is only applicable to a small subset of patients with high PD-L1 expre...Immune checkpoint inhibitors (ICI), epitomized by PD-1/PD-L1 antibodies, have ushered in a new era in lung cancer treatment. However, ICI monotherapy is only applicable to a small subset of patients with high PD-L1 expression, while most patients with low expression require combination therapies. In this study, we found that β-elemene promotes M1 polarization of tumor-associated macrophages (TAMs) and enhances the efficacy of PD-L1 antibody (aPD-L1) in C57BL/6 mice. RNA sequencing and surface plasmon resonance revealed that β-elemene directly binds to FLT1 and inhibits the PI3K/AKT/FOXO1 signaling pathway, thereby mediating TAMs M1 polarization. Using Flt1 knockout mice, we further validated the critical role of Flt1 in TAMs polarization and confirmed that M1 polarization synergizes with aPD-L1 treatment. Furthermore, co-immunoprecipitation showed that the FLT1 intracellular domain binds to and phosphorylates the p85α subunit, triggering downstream signaling cascades. These findings elucidate the synergistic mechanism between β-elemene and aPD-L1. Moreover, given the clinical availability of both agents, they provide a strong rationale for further clinical evaluation of this combination therapy.
Zhang G, Zhang W, Wei X
… +7 more, Wang Z, Wang F, Sun S, Xu H, Liu X, Zhang Q, Gao X
Cancer Immunol Immunother
· 2026 May · PMID 42101653
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Investigating strategies to enhance T cell effector function can improve the adoptive immune responses to tumors and complement existing tumor immunotherapies. Here, we present a novel artificially designed recombinant p...Investigating strategies to enhance T cell effector function can improve the adoptive immune responses to tumors and complement existing tumor immunotherapies. Here, we present a novel artificially designed recombinant protein, PK5-Gal-3C, which is composed of the fifth kringle domain of plasminogen (PK5) and the C-terminal carbohydrate-recognition domain of galectin-3 (Gal-3C). This protein exhibited potent anti-tumor activity by significantly enhancing T cell effector function. Specifically, PK5-Gal-3C directly activated T cells by binding to glycosylated TRPV2 via Gal-3C, a thermosensitive calcium-permeable cation channel, thereby promoting the influx of calcium ions to enhance T cells cytotoxicity via the activation of c-Jun. Correspondingly, inhibition of TRPV2 or c-Jun impaired the cytotoxicity of T cell mediated by PK5-Gal-3C. Additionally, PK5-Gal-3C demonstrated significant anti-tumor activity by enhancing T cell tumor infiltration and cytotoxicity in a mouse model, as well as improving the anti-tumor efficacy of CAR-T cells in solid tumors. In summary, PK5-Gal-3C is a safe and potent anti-tumor agent with promising potential for T cell-mediated cancer immunotherapy.
Suwanchiwasiri K, Somboonpatarakun C, Chaiyariti N
… +5 more, Suriya U, Chankhamhaengdecha S, Yenchitsomanus PT, Janvilisri T, Junking M
Cancer Immunol Immunother
· 2026 May · PMID 42098361
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Nasopharyngeal carcinoma (NPC) remains a highly aggressive malignancy with poor outcomes in advanced and recurrent disease. Although immune checkpoint inhibitors combined with chemotherapy improve survival, many patients...Nasopharyngeal carcinoma (NPC) remains a highly aggressive malignancy with poor outcomes in advanced and recurrent disease. Although immune checkpoint inhibitors combined with chemotherapy improve survival, many patients still experience relapse or disease progression. Here, we developed a non-genetically modified cellular immunotherapy based on αTrop2/αCD3 bispecific protein engager-armed T cells (αTrop2/αCD3-BATs), targeting Trop2, which is highly expressed in NPC and minimally expressed in normal tissues. Molecular dynamics simulations supported stable dual binding of the BiPE to Trop2 and CD3ε, consistent with effective immune synapse formation. Functionally, αTrop2/αCD3-BATs exhibited potent, antigen-dependent cytotoxicity against Trop2-positive NPC cell lines (TW01, HK1, and CNE1) in both two-dimensional co-culture and three-dimensional spheroid models while sparing Trop2-negative cells. Target engagement induced robust T cell activation and proliferation, accompanied by increased expression of effector molecules such as FasL and elevated secretion of cytolytic mediators (perforin, granzymes, and granulysin) and pro-inflammatory cytokines (IFN-γ, TNF-α, and IL-2). Collectively, these findings demonstrate that αTrop2/αCD3-BATs mediate potent and selective antitumor activity and support their further preclinical development as an MHC-independent cellular immunotherapy for Trop2-positive NPC.
Canaslan K, Nia FM, Baez M
… +19 more, Abolhassani H, Ridge N, Zerdan MB, Marks J, Rangoonwala H, Jahanbin B, Emami AH, O'Reilly K, Gökmen-Polar Y, Badve SS, Xu C, Hao Y, Sharma A, Upadhya S, Salle FG, Pan K, El Osta B, Shin DM, Ardeshir-Larijani F
Cancer Immunol Immunother
· 2026 May · PMID 42089900
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Koh HH, Lee S, Oum C
… +7 more, Song S, Cho SI, Pereira S, Ahn CH, Kim JY, Kim M, Jung M
Cancer Immunol Immunother
· 2026 May · PMID 42082707
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PURPOSE: The prognostic significance of tumor-infiltrating lymphocytes (TILs) in colorectal cancer (CRC) is well established; however, existing approaches inadequately capture their spatial distribution. We investigated...PURPOSE: The prognostic significance of tumor-infiltrating lymphocytes (TILs) in colorectal cancer (CRC) is well established; however, existing approaches inadequately capture their spatial distribution. We investigated the prognostic implications of TIL spatial distribution in CRC using an artificial intelligence (AI)-based method. METHODS: A total of 202 patients with stage II-III CRC were included. TIL densities in intratumoral (iTIL) and stromal (sTIL) regions were quantified using AI-based analysis of hematoxylin and eosin (H&E)-stained images. Based on proximity to the tumor-stromal border (TSB), TILs were subclassified into core iTIL, bounding iTIL, bounding sTIL, and outermost sTIL. Immunoscore was calculated from CD3 and CD8 T-cell densities in the tumor center and invasive margin. RESULTS: Correlations between AI-based and pathologist assessments (iTIL: r = 0.57; sTIL: r = 0.70) were comparable to inter-pathologist correlations (iTIL: r = 0.47; sTIL: r = 0.70). In univariate Cox regression analysis, bounding iTIL, bounding sTIL, and outermost sTIL were significantly associated with recurrence-free survival (RFS), whereas core iTIL was not. Composite TIL and TSB scores were developed by incorporating the prognostically significant regions. In multivariable analysis, the TIL score (p = 0.001), TSB score (p < 0.001), and Immunoscore (p < 0.001) independently predicted RFS. In microsatellite instability-high tumors, only the TSB score remained prognostically significant. CONCLUSION: AI-powered spatial analysis of TILs, particularly the TSB score, demonstrated prognostic performance comparable to conventional Immunoscore, thereby supporting the value of spatial immune profiling and AI-driven analysis of H&E-stained slides for improved risk stratification in CRC.
Zhai Y, Yu Y, Bao R
… +7 more, Liu J, Fang J, Lu W, Zhang D, Guo H, Yao Y, Shi J
Cancer Immunol Immunother
· 2026 May · PMID 42082682
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Venetoclax plus hypomethylating agents (HMAs) is a standard therapy for older or unfit patients with acute myeloid leukemia (AML); however, some patients exhibit suboptimal responses, potentially associated with T-cell e...Venetoclax plus hypomethylating agents (HMAs) is a standard therapy for older or unfit patients with acute myeloid leukemia (AML); however, some patients exhibit suboptimal responses, potentially associated with T-cell exhaustion. Our preclinical findings that statins enhance HMA efficacy by boosting anti-tumor T-cell responses prompted us to translate this strategy to the clinic. A multicenter phase II clinical trial (ChiCTR 2500111931) was conducted to evaluate the efficacy and safety of adding rosuvastatin to venetoclax and azacitidine (venetoclax-azacitidine) in older/unfit AML patients. After induction therapy with this triple combination, the cohort achieved a complete response (CR) rate of 55.5% and a composite complete remission (CRc) rate of 72.2%. Among patients who achieved CRc, 84.6% attained measurable residual disease (MRD) < 10. With a median follow-up of 10 months, the median overall survival (OS) and relapse-free survival (RFS) were 18 and 14 months, respectively. Although no significant changes in lipid profiles were observed, multiparametric flow cytometry revealed significant reductions in PD-1⁺CD4⁺ T cells (p = 0.0137) and PD-1⁺CD8⁺ T cells (p = 0.0277) after therapy. In vitro experiments revealed that the addition of rosuvastatin diminished both early (PD-1⁺TIM-3⁻) and terminally (PD-1⁺TIM-3⁺) exhausted T cells, suggesting it prevents the development of T-cell exhaustion induced by venetoclax-azacitidine. Furthermore, functional assays confirmed that rosuvastatin addition significantly enhanced T cell cytotoxicity against leukemia cells. Collectively, our findings suggest that adding rosuvastatin to venetoclax-azacitidine shows preliminary clinical activity and acceptable safety, possibly by reducing T-cell exhaustion, thus supporting further study of this triple regimen in older/unfit AML patients.
Nurmela V, Schroderus AM, Tiainen S
… +8 more, Kuittinen O, Tenhunen O, Jokimäki A, Suoranta S, Pasonen-Seppänen S, Sievänen T, Kinnunen T, Rönkä A
Cancer Immunol Immunother
· 2026 May · PMID 42068384
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Immune checkpoint inhibitors (ICI) have transformed the treatment of metastatic malignancies, yet only 20-40% of unselected patients benefit. Peripheral blood could offer a minimally invasive and dynamic source for predi...Immune checkpoint inhibitors (ICI) have transformed the treatment of metastatic malignancies, yet only 20-40% of unselected patients benefit. Peripheral blood could offer a minimally invasive and dynamic source for predictive biomarkers of ICI therapy.This study evaluated circulating immune cell frequencies and phenotypes before and during ICI therapy to identify tumor-agnostic blood-based biomarkers. We analyzed routine blood immune cell counts in a retrospective cohort of 202 patients treated with ICIs. Next, we investigated the findings in a prospectively collected cohort of 45 patients using multiparametric flow cytometry for characterization of immune cell subsets. We considered early radiological response, progression-free survival (PFS), and overall survival (OS) as clinical outcomes.Higher pre-treatment monocyte and lower lymphocyte counts were consistently associated with inferior PFS and OS but not with early radiological response in the retrospective cohort. In the prospective cohort, detailed immunophenotyping identified elevated pre-treatment frequencies of intermediate (CD14⁺CD16⁺) monocytes as a marker of poorer PFS and OS. Within lymphocyte subsets, higher T cell frequencies were associated with better OS, and a higher pre-treatment frequency of CD226-expressing CD8⁺ memory T cells with better ICI response. ICI therapy induced increase in TIGITCD8 and CD4 memory T cell subsets, regardless of treatment response.In conclusion, elevated pre-treatment levels of blood monocytes, together with decreased levels lymphocytes, were associated with poor survival of ICI-treated patients. Although detailed immunophenotyping of pre-treatment blood immune cell populations showed limited predictive utility, specific subpopulations, such as intermediate monocytes and CD226⁺CD8⁺ memory T cells, may harbor potential as prognostic/predictive indicators.
Li C, Zhang P, Zhao X
… +7 more, Feng R, Xian N, Huang G, Jiang W, Hu Z, Zhang Y, Ji N
Cancer Immunol Immunother
· 2026 May · PMID 42068336
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Locoregional CAR-T delivery is increasingly explored for glioblastoma to improve intracranial tumor exposure; however, organ-level biodistribution kinetics after intracranial administration remain poorly quantified in vi...Locoregional CAR-T delivery is increasingly explored for glioblastoma to improve intracranial tumor exposure; however, organ-level biodistribution kinetics after intracranial administration remain poorly quantified in vivo, limiting route-informed optimization and preclinical risk assessment. Here, we report a dual-modality cell labeling and tracking strategy based on indocyanine green-conjugated iron nanoparticles (ICG-NPs) for in vivo assessment of B7-H3-targeting CAR-T cell (TX103) biodistribution using second near-infrared window (NIR-II) fluorescence imaging and magnetic resonance imaging (MRI). Using a heparin-protamine-assisted protocol, TX103 cells were labeled with high efficiency (83.1%) without detectable changes in viability, CAR expression, immunophenotype (including activation/exhaustion marker profile and CXCR3 expression), or cytotoxic function. In vitro imaging demonstrated a linear correlation between NIR-II fluorescence intensity and labeled cell numbers (R = 0.973, p < 0.001), while MRI provided complementary anatomical context at higher cell densities. In an orthotopic glioma mouse model, longitudinal MRI and NIR-II imaging captured route-dependent differences in tumor-associated localization and whole-body biodistribution following intracerebroventricular and intravenous administration. Furthermore, organ-level NIR-II exposure showed a positive association with CD3⁺ T-cell density across organs (R = 0.552, p < 0.001), supported by multi-organ pathological validation. Collectively, we establish a biocompatible dual-modality workflow that links intracranial anatomical localization with longitudinal whole-body biodistribution readouts for preclinical CAR-T tracking in solid tumor models.
Ren Z, Huang Y, Guo Y
… +14 more, Hou MM, Wang W, Kuang M, Hao C, Wang W, Zhang Y, Song T, Dai C, Kuo HT, Bao Z, Zuo Y, Wang L, Zhu F, Fan J
Cancer Immunol Immunother
· 2026 Apr · PMID 42047833
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BACKGROUND: Patients with hepatocellular carcinoma (HCC) have an unmet need for new therapies that improve survival. This phase II trial investigated the efficacy and safety of ociperlimab and tislelizumab plus BAT1706 (...BACKGROUND: Patients with hepatocellular carcinoma (HCC) have an unmet need for new therapies that improve survival. This phase II trial investigated the efficacy and safety of ociperlimab and tislelizumab plus BAT1706 (a bevacizumab biosimilar) in patients with first-line HCC. METHODS: In this phase II, multicenter, randomized, multi-arm, open-label trial, patients with advanced HCC received ociperlimab and tislelizumab plus BAT1706 (Arm A) or tislelizumab plus BAT1706 (Arm B). The primary objective was to evaluate efficacy using objective response rate (ORR) assessed by the investigator per RESIST v1.1 for Arms A and B. RESULTS: 94 patients were randomized to Arm A (N = 62) and Arm B (N = 32). Confirmed ORR (95% confidence interval) was 37.1% (25.2-50.3) for Arm A and 40.6% (23.7-59.4) for Arm B. In Arms A and B, respectively, 90.3% and 80.6% of patients experienced treatment-related treatment-emergent adverse events (TEAEs), 59.7% and 32.3% experienced Grade ≥ 3 treatment-related TEAEs and 22.6% and 9.7% experienced treatment-related TEAEs leading to treatment discontinuation. Immune-mediated adverse events were reported in 50.0% of patients in Arm A and 45.2% of patients in Arm B. Infusion-related reactions occurred in a single patient in Arm A. CONCLUSION: In patients with advanced HCC, tislelizumab plus BAT1706 demonstrated promising ORR, while adding ociperlimab was not associated with improved efficacy. The safety profile of ociperlimab and tislelizumab plus BAT1706 was tolerable and manageable, with no new safety signals identified. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04948697 (September 20, 2021).
Gámez-Pozo A, Trilla-Fuertes L, Becerril-Gómez F
… +18 more, Lalanda-Delgado P, Soriano V, Garicano Goldaraz F, Lecumberri MJ, Rodríguez de la Borbolla M, Majem M, Pérez-Ruiz E, González-Cao M, Oramas J, López-Vacas R, Magdaleno A, Fra J, Martín-Carnicero A, Corral M, Puértolas T, Ramos-Ruiz R, Espinosa E, Fresno Vara JÁ
Cancer Immunol Immunother
· 2026 Apr · PMID 42047827
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BACKGROUND: Immunotherapy based on anti-PD1 inhibitors has significantly improved survival in advanced melanoma. However, a significant proportion of patients do not benefit, and predicting response to immunotherapy rema...BACKGROUND: Immunotherapy based on anti-PD1 inhibitors has significantly improved survival in advanced melanoma. However, a significant proportion of patients do not benefit, and predicting response to immunotherapy remains an area of unmet need. Our group previously defined an immune signature able to predict response to anti-PD1 inhibitors in this scenario. METHODS: In this study, we analyzed two cohorts of patients with advanced melanoma treated with anti-PD1 inhibitors: the GEM cohort, previously used to validate our immune signature, and Campbell's cohort, which contains data about different immunotherapy schemes. Using the 107 genes that compose our immune signature and consensus clustering, samples were classified as immune-low or immune-high. Then, CIBERSORTx and Ecotyper were used to estimate the proportion of each immune cell type and carcinoma ecotypes in both cohorts. RESULTS: We confirmed that the immune-low group includes mostly patients who do not response to anti-PD1 inhibitors. We also studied the distribution of carcinoma ecotypes in the immune-high and immune-low groups defined by our immune classification. Ecotypes CE9 and CE10 clustered in the immune-high group, with good response to treatment. The use of combination immunotherapy improved response rate both in immune-low and immune-high tumors. The immune-high group contained a higher number of CD8 T cells, B memory cells and T follicular helper cells. CONCLUSIONS: Our immune-based classification defines an immune-low group of tumors with poor response to anti-PD1 inhibitors. This immune classification is related to carcinoma ecotypes. Finally, a use of a combo scheme improves the rates of response both in immune-high and low groups but in the case of immune-low tumors, our results suggests that a combo treatment approach could be an adequate strategy and should be further explored in these patients. Altogether, our results support the utility of our immune signature in the prediction of response to anti-PD1 inhibitors in advanced melanoma.
Kamigaichi A, Kagamu H, Miyata Y
… +4 more, Mimae T, Tsubokawa N, Hirano K, Okada M
Cancer Immunol Immunother
· 2026 Apr · PMID 42047825
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INTRODUCTION: Tumor-draining lymph nodes (LNs) are critical for initiating and maintaining antitumor immunity. However, systematic LN dissection (LND) remains the standard surgical procedure for lung cancer. This study a...INTRODUCTION: Tumor-draining lymph nodes (LNs) are critical for initiating and maintaining antitumor immunity. However, systematic LN dissection (LND) remains the standard surgical procedure for lung cancer. This study aimed to investigate the immunological impact of tumor-draining LND on systemic T cell subsets. METHODS: We prospectively analyzed perioperative peripheral blood and resected LN samples from patients with early-stage lung adenocarcinoma who underwent lobectomy with systematic LND (systematic LND group) or wedge resection without LND (LN-preserving group). Perioperative immune cell dynamics were comprehensively profiled using mass cytometry. RESULTS: Unlike conventional CD4 and CD8 T cell subsets, Th7R (CXCR3CCR4CCR6 CD62LCD4 T cell), a Th1-like CD4 T cell cluster essential for antitumor immunity, consistently decreased in peripheral blood after tumor resection in both groups (p = 0.0016 and p = 0.0033). This decline was significantly milder in the LN-preserving group than in the systematic LND group (p = 0.0153). In LN analyses, Th7R percentages were significantly higher in hilar, interlobar, and peripheral LNs than in subcarinal and other mediastinal LNs (p = 0.0148). Th7R percentages in resected LNs strongly and negatively correlated with postoperative changes in peripheral blood (r = -0.857, p = 0.0137). Furthermore, greater declines in Th7R in peripheral blood were associated with postoperative oncological disease events. CONCLUSIONS: Preserving LNs contributes to maintaining systemic antitumor immunity after surgery for early-stage lung cancer. Hilar, interlobar, and peripheral LNs may serve as primary reservoirs and supply sources of Th7R. In early-stage disease, these findings suggest a potential immunological benefit of LN-preserving strategies.
Feng J, Liu J, Yang H
… +5 more, Li Y, Xu Y, Han X, Zhang C, Wang G
Cancer Immunol Immunother
· 2026 Apr · PMID 42047819
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BACKGROUND: The role of extrachromosomal DNA (ecDNA)-related genes in osteosarcoma remains largely unexplored. The aim of this study is to investigate the association between ecDNA-related genes and prognosis and tumor m...BACKGROUND: The role of extrachromosomal DNA (ecDNA)-related genes in osteosarcoma remains largely unexplored. The aim of this study is to investigate the association between ecDNA-related genes and prognosis and tumor microenvironment (TME) in osteosarcoma. METHODS: Differential gene expression analysis of GEO datasets was conducted to identify ecDNA-related genes in osteosarcoma. Based on bulk RNA-seq data, a novel ecDNA-related Gene Prognostic Score Model (EGPSM) was developed using an integrated framework of 101 machine learning algorithms, which was validated in training, testing, and external cohorts. The associations between risk scores, prognosis, and TME characteristics were comprehensively evaluated. Single-cell RNA sequencing (scRNA-seq) data were further analyzed to elucidate the relationship between EGPSM, pro-tumor behaviors, and immune modulation in osteosarcoma, as well as to identify key prognostic genes involved in tumor progression. Lastly, we conducted in vitro and in vivo assays to characterize the biological roles of MTDH and to elucidate its regulatory effects on CD8⁺ T cell function. RESULTS: A robust EGPSM was constructed, demonstrating superior predictive accuracy with a maximum C-index of 0.803. High-risk patients exhibited poorer survival, higher metastatic potential, and an "immune-cold" TME characterized by diminished CD8⁺ T/NK cell infiltration and impaired effector functions. Single-cell analysis confirmed the enrichment of malignant cells and depletion of T/NK populations with lower effector scores in the high-risk group. MTDH was identified as a key driver; functional assays showed it promotes proliferation and invasion while inhibiting apoptosis. Notably, MTDH knockdown potentiated CD8⁺ T-cell cytotoxicity by increasing the levels of granzyme B, IFN-γ, and perforin. CONCLUSION: The newly developed EGPSM represents an effective tool for prognostic assessment and therapeutic stratification in osteosarcoma. MTDH may serve as a promising prognostic biomarker and therapeutic target.
Cinotti R, Geindreau M, Bergqvist A
… +2 more, Yang Y, Lundqvist A
Cancer Immunol Immunother
· 2026 Apr · PMID 42020832
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High frequency and activity of tumor-infiltrating natural killer (NK) cell is associated with improved prognosis in several solid cancers including non-small cell lung cancer. However, multiple factors can suppress NK ce...High frequency and activity of tumor-infiltrating natural killer (NK) cell is associated with improved prognosis in several solid cancers including non-small cell lung cancer. However, multiple factors can suppress NK cell activity within the tumor microenvironment, resulting in impaired killing of tumor cells. For NK cells to engage and kill target cells, stabilization of lipid rafts is essential. Sphingomyelin is involved in lipid raft formation and is catabolized by sphingomyelinases. While inhibition of sphingomyelinases enhances NK cell-mediated killing of tumor cells, it is unknown how sphingomyelinases impact on the ability of NK cells to infiltrate solid tumors. Here we demonstrate that inhibition of sphingomyelinases results in increased activation and ability of NK cells to infiltrate lung adenocarcinoma. Overall, our findings support the use of sphingomyelinase inhibitors as enhancers of NK cell activation.
Furriel F, Laranjeira P, Pereira M
… +7 more, Silva S, Silva I, Fontinha G, Sousa V, Gomes C, Parada B, Paiva A
Cancer Immunol Immunother
· 2026 Apr · PMID 42018002
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Urothelial bladder cancer (BCa) is marked by high recurrence and mortality, and the efficacy of PD-1/PD-L1 immunotherapy remains limited because of immune evasion. The adenosinergic pathway (AP), mediated by ectonucleoti...Urothelial bladder cancer (BCa) is marked by high recurrence and mortality, and the efficacy of PD-1/PD-L1 immunotherapy remains limited because of immune evasion. The adenosinergic pathway (AP), mediated by ectonucleotidases CD39 and CD73, is a key immunosuppressive mechanism, but its role in BCa remains unclear. We conducted an integrated immunophenotypic analysis of peripheral blood (PB) and the tumor microenvironment (TME) from 39 patients with BCa and 14 healthy controls using multicolor flow cytometry and immunohistochemistry. High-risk (HR) patients exhibited systemic immunosuppression, characterized by an elevated neutrophil-to-lymphocyte ratio and increased circulating regulatory T cells (Tregs), along with reduced cytotoxic γδ T cells and diminished Th1/Tc1 functional subtypes. In the TME, we observed reduced CD8 T cell infiltration accompanied by increased Tregs, and phenotypes characterized by poor immune infiltration in the tumor core predominated across the cohort. In both PB and the TME, CD39 and CD73 expression on T cells strongly correlated with an immunosuppressive environment, marked by increased M2-like macrophages and decreased effector T cells. Circulating double-positive T cells (CD4CD39CD73 and CD8CD39CD73) mirrored the intratumoral T-cell composition, suggesting their potential as non-invasive biomarkers. Elevated frequencies of circulating single-positive CD8CD39 and CD8CD73 T-cells were significantly associated with higher pathological grade and distinguished high-grade tumors with moderate accuracy (AUC > 0.70). This study demonstrates that BCa is characterized by extensive AP-linked immunosuppression, and that specific ectonucleotidase-expressing circulating T-cell subsets may serve as non-invasive biomarkers for assessing tumor infiltration and grade.