Cancer Immunology, Immunotherapy[JOURNAL]
Sun
200 papers
Repurposing public sarcoma multi-omics for neoantigen discovery.
Mantas P, Krogfelt KA
Cancer Immunol Immunother · 2026 Apr · PMID 42012689 · Full text
BACKGROUND: Soft tissue sarcomas, particularly complex karyotype sarcomas (CKS), are characterized as "immunologically cold" malignancies driven by structural instability rather than a high tumor mutational burden (TMB)....
BACKGROUND: Soft tissue sarcomas, particularly complex karyotype sarcomas (CKS), are characterized as "immunologically cold" malignancies driven by structural instability rather than a high tumor mutational burden (TMB). Public "legacy" cohorts are a useful resource to uncover immunotherapy biomarkers. This study used the whole-exome sequencing (WES) and RNA-sequencing of CKS patients, to overcome technical limitations and to identify and prioritize neoantigens. METHODS: The systematic immunogenomic reanalysis was performed on a landmark cohort of CKS patients (Kim et al., 2018) with a custom bioinformatics workflow which was developed to uncover interpretable immunogenomic signals. This approach consisted of: (1) defining a quality-controlled "callable territory" and normalizing TMB metrics, respectively; (2) utilizing RNA-seq not only for expression filtering but as an orthogonal validation check for variant transcription and to distinguish functional amplifications from technical depth artifacts; and (3) applying a multi-modal epitope prediction pipeline to identify and prioritize high-affinity neoantigens derived from both somatic SNVs, indels and expressed gene fusions. RESULTS: The reanalysis shows that standard genome-wide metrics frequently underestimated the immunogenic potential. Normalizing the TMB refined quantitative mutation burden estimates and improved interpretation of low-coverage samples without essentially changing the overall cohort classification. Furthermore, integration of transcriptomic data facilitated the recovery of actionable targets in "low-TMB" tumors. A subset of fusion-derived peptides demonstrated predicted binding affinities competitive with SNV-derived candidates. CONCLUSION: This study illustrates that technically constrained multi-omic datasets can be systematically re-analyzed to identify potential therapeutic targets. These data argue for looking beyond aggregate biomarkers; patient-specific, expressed neoepitopes may exist even in sarcomas typically described as immunologically "cold".
Envafolimab combined with lenvatinib and albumin-bound paclitaxel in previously treated advanced gastric/gastroesophageal junction (G/GEJ) adenocarcinoma: a prospective, phase II, multi-cohort trial.
Xiaoying Z, Wanjing F, Qirong G … +6 more , Mingzhu H, Zhe Z, Jinsi C, Xuedan S, Xiaodong Z, Weijian G
Cancer Immunol Immunother · 2026 Apr · PMID 42012665 · Full text
BACKGROUND: This single-center, open-label, exploratory trial aimed to investigate the efficacy and safety of envafolimab combined with lenvatinib and chemotherapy in previous treated advanced G/GEJ adenocarcinoma. METHO...
BACKGROUND: This single-center, open-label, exploratory trial aimed to investigate the efficacy and safety of envafolimab combined with lenvatinib and chemotherapy in previous treated advanced G/GEJ adenocarcinoma. METHODS: Eligible patients with HER2-negative, microsatellite stable (MSS) advanced G/GEJ adenocarcinoma who had progressed after first-line treatment were enrolled in this phase II trial. Patients without previously receiving PD-1/PD-L1 inhibitors were enrolled in Group A, and those who progressed on the first-line PD-1 inhibitors were included in Group B. Patients in both groups received envafolimab (200 mg, subcutaneous injection (sc), days 1 and 15, Q4W) combined with lenvatinib and albumin-bound paclitaxel (100 mg/m, IV, days 1, 8 and 15, Q4W, up to 6 cycles) until disease progression, unacceptable toxicity, or refusal of continuation. The primary endpoint was objective response rate (ORR). RESULTS: A total of 30 patients were included for safety and efficacy analysis. As of data cutoff (Sep 14, 2024), the median follow-up was 17.0 months (IQR: 8.0-18.8) in Group A. The ORR was 60.0%, and the DCR was 100.0%. The mPFS was 8.2 months (95% CI 6.1-10.4) with mOS of 14.8 months (95% CI 7.4-22.2). With a median follow-up of 9.0 months (IQR: 6.1-16.2) in Group B, the ORR was 46.7%, and the DCR was 100.0%. The mPFS was 5.9 months (95% CI 3.8-8.1), and the mOS was 11.5 months (95% CI 3.1-19.9). The overall incidence of adverse events (AEs) of any grade was 100%. While Group A showed numerically better outcomes than Group B, there was no statistically significant difference in PFS (P = 0.629) or OS (P = 0.873) between the two groups. CONCLUSIONS: Second-line envafolimab-based combination therapy demonstrated promising effects in previously treated advanced GC, particularly in those who have not previously received ICIs.
IL-18-armed oncolytic vaccinia virus remodels the suppressive microenvironment via macrophage and Treg modulation in lymphoma.
Wu H, Zhang J, Xu L … +8 more , Xie Y, Pan L, Zhang X, Xia Y, Yang F, Kang X, Tong X, Wang S
Cancer Immunol Immunother · 2026 Apr · PMID 42012649 · Full text
INTRODUCTION: Lymphoma is a heterogeneous hematological malignancy with limited effective therapies. Oncolytic vaccinia virus (OVV) is a promising immunotherapy, but its monotherapeutic efficacy is suboptimal, showing we...
INTRODUCTION: Lymphoma is a heterogeneous hematological malignancy with limited effective therapies. Oncolytic vaccinia virus (OVV) is a promising immunotherapy, but its monotherapeutic efficacy is suboptimal, showing weak antitumor activity in murine lymphoma models and inducing an immunosuppressive tumor microenvironment (TME) with more M2 macrophages and Tregs. This study aimed to improve OVV's efficacy and translational feasibility by reversing the immunosuppressive TME and enhancing OVV-mediated antitumor immunity. METHODS: We first explored IL-18's effect on OVV-induced immunosuppressive TME, then engineered a recombinant OVV-hIL18 encoding human IL-18. We assessed its in vitro oncolytic activity, in vivo antitumor effect and safety in murine/humanized lymphoma models, and its TME-regulating mechanisms. RESULTS: IL-18 reversed OVV-induced immunosuppression by promoting M1 polarization and reducing Tregs, boosting OVV-mediated immunity. OVV-hIL18 had enhanced in vitro oncolysis, significantly inhibited tumor growth, prolonged survival in animal models without overt toxicity, and increased CD4⁺/CD8⁺ T cell infiltration, effector cytokine production and relieved T cell exhaustion in TME. CONCLUSION: IL-18-armed OVV overcomes OVV monotherapy limitations and enhances antitumor efficacy, providing theoretical and experimental support for its development as a next-generation immunotherapy for lymphoma.
KSR2 functions as a metabolic checkpoint for anti-PD-1 resistance by reprogramming glucose metabolism.
Ge Y, Zhou Q, Zhang Q … +2 more , Hu Y, Wang R
Cancer Immunol Immunother · 2026 Apr · PMID 42012646 · Full text
Immune checkpoint blockade targeting the PD-1/PD-L1 axis has revolutionized cancer therapy, yet the frequent emergence of resistance limits its clinical efficacy. Elucidating the mechanisms underlying resistance and deve...
Immune checkpoint blockade targeting the PD-1/PD-L1 axis has revolutionized cancer therapy, yet the frequent emergence of resistance limits its clinical efficacy. Elucidating the mechanisms underlying resistance and developing effective strategies remain critical challenges in tumor immunotherapy. This study identifies kinase suppressor of Ras 2 (KSR2) as a driver of resistance to anti-PD-1 therapy in lung cancer. Transcriptomic analysis of an anti-PD-1-resistant mouse model and public clinical datasets revealed upregulation of KSR2 in resistant tumors. In vivo functional studies demonstrated that KSR2 overexpression is sufficient to confer resistance, while its knockdown resensitizes tumors to PD-1 blockade. Mechanistically, KSR2 functions as a central metabolic checkpoint, driving profound glucose metabolic reprogramming in cancer cells by enhancing glucose uptake, potentiating the Warburg effect, promoting lactate accumulation, and disrupting the tricarboxylic acid cycle. This metabolic reprogramming was subsequently associated with an immunosuppressive tumor microenvironment, characterized by reduced infiltration and impaired function of CD8⁺ T cells, alongside an enrichment of regulatory T cells. These findings suggest that KSR2 plays a role in modulating immunotherapy response, indicating a potential link between tumor metabolism and immune evasion. KSR2 emerges as a candidate target for further exploration in overcoming anti-PD-1 resistance.
Identification and prioritisation of tumour antigen candidates from 79 glioblastoma transcriptomes.
Kert Š, Pižem J, Petrin S … +4 more , Bošnjak M, Jerala M, Matjašič A, Zupan A
Cancer Immunol Immunother · 2026 Apr · PMID 42012534 · Full text
Glioblastoma (GBM) is an aggressive brain tumour with limited responsiveness to current immunotherapeutic approaches, partly due to its low mutational burden and intra-tumour heterogeneity. A systematic understanding of...
Glioblastoma (GBM) is an aggressive brain tumour with limited responsiveness to current immunotherapeutic approaches, partly due to its low mutational burden and intra-tumour heterogeneity. A systematic understanding of the tumour antigen landscape is therefore essential for advancing tumour immunology and supporting rational development of immunotherapeutic strategies. In this study, we performed whole-transcriptome sequencing of RNA extracted from 79 formalin-fixed paraffin-embedded (FFPE) IDH-wildtype GBM samples to systematically identify and prioritise candidate tumour antigens derived from three sources: single-nucleotide variants (SNVs), overexpressed tumour-associated antigens (TAAs), and gene fusion events. Candidate peptides were evaluated using integrated computational criteria, including transcript expression, predicted antigen processing features, peptide-HLA binding affinity and stability. Across the cohort, mutation-derived tumor-specific antigens (TSAs) were largely private to individual samples, whereas TAAs constituted a larger and more recurrent candidate pool. Despite comparable predicted binding characteristics across antigen classes, recurrence patterns differed substantially, reflecting their distinct biological origins. Fusion-derived candidates were rare and sample-specific. Predicted peptide presentation was disproportionately associated with a limited subset of HLA class I alleles. Collectively, this study provides a systematically prioritized catalogue of transcriptionally expressed GBM antigen candidates and offers a comparative evaluation of mutation-, expression-, and fusion-derived antigen sources within a unified transcriptome-based framework.
Targeting Blimp-1 in T cells results in activation of T-bet-mediated control of immunosuppression in lung cancer.
Finotto S, Chiriac MT, Krammer S … +9 more , Yang Z, Neurath L, Geppert CI, Nendel E, Trump S, Geiger A, Wirtz S, Zundler S, Neurath MF
Cancer Immunol Immunother · 2026 Apr · PMID 41984247 · Full text
BACKGROUND: Lung cancer is the leading cause of cancer-related death in the world. Blimp-1 is a transcriptional repressor that, by interacting with other transcription factors in lymphocytes, regulates their cellular fat...
BACKGROUND: Lung cancer is the leading cause of cancer-related death in the world. Blimp-1 is a transcriptional repressor that, by interacting with other transcription factors in lymphocytes, regulates their cellular fate. OBJECTIVE: In this study, we focused on the role of Blimp-1 in T cells in lung cancer. METHODS: Here, we analyzed, in a murine model of NSCLC, the role of Blimp-1 in T cells after targeting Blimp-1 in T cells expressing lymphocyte-specific-protein tyrosine kinase (Lck), a kinase crucial for T-cell receptor signaling. RESULTS: We found that mice lacking Blimp1 expression in T cells have reduced lung tumor load, suppressed lung Foxp3+Treg cells in the lung and draining lymph nodes, and induced T-bet+CD4+T effector cells producing IFN-gamma and interleukin-2. Furthermore, RNA sequencing of spleen CD4+T cells showed an induction of Th1 markers, including TNF, IL-2 and interferon type I-related genes, but also PD1. RNA sequencing of spleen CD8+T cells showed induced Tc1 markers, including IL12rb1, CD44, granzyme M and eomesodermin, in the absence of Blimp1. Finally, in the lung of mice with Blimp1 deficiency in T cells, we found an upregulation of CD8+T cells with increased release of cytotoxic mediators able to induce lung tumor cell death. CONCLUSIONS: These data indicate that the tumor microenvironment induces Blimp-1 in immunosuppressive Treg and T effector cells, thereby limiting the therapeutic efficacy of anti-tumor immune responses. Targeting of Blimp-1 in T cells emerges as a novel concept to suppress immune evasion in lung cancer by regulating CD4+, CD8+and Treg function in the lung.
Hematological toxicities and thrombosis risk associated with immune checkpoint inhibitors: a pharmacovigilance study from 2014 to 2024.
Hou J, Mu G, Zhang Z … +2 more , Xiang Q, Cui Y
Cancer Immunol Immunother · 2026 Apr · PMID 41984243 · Full text
BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes in a wide range of cancers but may also induce hematological toxicities and thrombosis risk. This study comprehensively evalua...
BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes in a wide range of cancers but may also induce hematological toxicities and thrombosis risk. This study comprehensively evaluated hematological and thrombotic adverse events (AEs) associated with ICIs in real-world settings using the FDA Adverse Event Reporting System (FAERS) database, aiming to characterize their clinical features. METHODS: Data were extracted from the FAERS database (Q1 2014 to Q4 2024) for disproportionality analysis. AEs were classified using the Medical Dictionary for Regulatory Activities (MedDRA). Associations between ICIs and hematological/thrombotic AEs were assessed via the reporting odds ratio (ROR) and Bayesian Confidence Propagation Neural Network (BCPNN) methods. Clinical characteristics of affected patients were analyzed, and time-to-onset across ICI regimens was further evaluated. RESULTS: We identified 14,753 ICI-associated hematological toxicities and thrombotic events. Among reports with available sex information, a higher reporting frequency was observed in men (50.90%) than in women (40.11%). The most frequent AEs were anemia (2963 cases, 16.62%), thrombocytopenia (1961, 11.00%), febrile neutropenia (1935, 10.85%), neutropenia (1392, 7.81%), myelosuppression (979, 5.49%), pancytopenia (739, 4.14%), lymphadenopathy (475, 2.66%), disseminated intravascular coagulation (DIC; 468, 2.62%), leukopenia (468, 2.62%), and deep vein thrombosis (DVT; 213, 1.19%). The median time-to-onset for ICI monotherapy-associated AEs was 28 days (IQR 11-79), with 78.22% occurring within 3 months. Notably, DIC and DVT had the highest mortality proportion among the top 10 AEs. CONCLUSION: Hematological and thrombotic AEs associated with ICI therapy show notable reporting frequencies in FAERS. Combination regimens demonstrated stronger reporting signals for certain events. These AEs frequently showed early reporting and notable mortality proportions, highlighting the importance of clinical vigilance. Further studies are needed to confirm these findings.
Radiation-induced remodeling of the T cell landscape in head and neck cancer.
Memon AA, Said I, Norenberg E … +14 more , Frei A, Foeckler J, Sun F, Dwinell MB, Lochhead RB, Bruening J, Akakpo K, Massey B, Wong SJ, Hematti P, Kearl TJ, Awan MJ, Himburg HA, Zenga J
Cancer Immunol Immunother · 2026 Apr · PMID 41984232 · Full text
Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy associated with high recurrence rates and substantial treatment-related morbidity. Radiation therapy remains a central component of the management...
Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy associated with high recurrence rates and substantial treatment-related morbidity. Radiation therapy remains a central component of the management of locoregional disease. Although radiation directly damages malignant cells through DNA breaks and associated stress pathways, radioresistance remains common, and a proportion of patients continue to develop locoregional recurrence or distant metastasis despite adequate locoregional control. Recent advances in single-cell and spatiotemporal profiling of HNSCC have clarified how radiation alters systemic and intra-tumoral T cell populations and produces a post-radiation tumor microenvironment that provides insufficient support for the robust priming of new tumor-reactive responses. These insights help explain why clinical trials combining radiotherapy with immune checkpoint inhibitors have not reproduced the synergy predicted by preclinical models. At the same time, they point to opportunities to design radiation as a programmable immune adjuvant. In this review, we summarize emerging mechanistic data on radiation-induced remodeling of the T cell landscape, outline the barriers that limit productive immune priming after treatment, and discuss strategies aimed at restoring effective anti-tumor immunity in the post-radiation setting.
Immunotherapy for pediatric solid tumors: overcoming biological barriers through rational multimodal combinations.
Fatahichegeni M, Ansarian MA, Xiao M … +2 more , Gao W, Shi R
Cancer Immunol Immunother · 2026 Apr · PMID 41984108 · Full text
Pediatric solid tumors remain among the most treatment-refractory childhood malignancies, defined by biological features that have largely resisted the immunotherapeutic advances transforming adult oncology. Exceptionall...
Pediatric solid tumors remain among the most treatment-refractory childhood malignancies, defined by biological features that have largely resisted the immunotherapeutic advances transforming adult oncology. Exceptionally low tumor mutational burden, sparse neoantigen landscapes, and profoundly immunosuppressive tumor microenvironments collectively undermine the T cell-dependent mechanisms on which most current immunotherapies depend. Yet the field is undergoing a meaningful shift. Anti-GD2 monoclonal antibodies have established a survival benchmark in high-risk neuroblastoma, and next-generation antibody-drug conjugates and bispecific T cell engagers targeting GD2, B7-H3, and GPC2 are extending the reach of antibody-based approaches across pediatric histologies. CAR T cell therapies have demonstrated clinical feasibility against multiple targets, with advanced engineering strategies, including cytokine armoring, bispecific constructs, and locoregional delivery, beginning to address fundamental barriers such as poor tumor infiltration, limited persistence, and antigen escape. Immune checkpoint inhibitors, while largely ineffective as monotherapy in unselected populations, induce durable responses in molecularly defined subsets such as mismatch repair-deficient and hypermutated tumors. Emerging platforms, including oncolytic virotherapy, NK cell engagers, and neoantigen vaccines, offer rational strategies to convert immunologically cold tumors into treatment-responsive phenotypes. Together, these advances point toward a future of combination immunotherapy tailored to the distinct immune biology of childhood cancers.
Promoting APC function of B cells via reprogramming the fatty acid metabolism enhances anticancer immunity in metastatic ovarian cancer.
Zhang H, Yu C, Du W … +15 more , Li H, Liu Z, Li X, Yue Y, Wang B, Wang H, Ouyang Y, Wu H, Feng X, Yu J, Liu Y, Ji B, Cai S, Zhang H, Deng W
Cancer Immunol Immunother · 2026 Apr · PMID 41984099 · Full text
B cells have become one of the important participants in anti-tumor immunity. Compared with DCs and macrophages, B cells have unique advantages in presenting low-abundance antigens to T cells. Fatty acids play a key role...
B cells have become one of the important participants in anti-tumor immunity. Compared with DCs and macrophages, B cells have unique advantages in presenting low-abundance antigens to T cells. Fatty acids play a key role in the metabolic adaptation of B cells. Whether the APC function of B cells can be enhanced through reprogramming fatty acid metabolism in the tumor microenvironment (TME) is worthy of study. Ovarian cancer (OvCa) is a gynecological malignant tumor with a high mortality rate. Most patients in the advanced stage often have extensive omental metastasis and ascites formation, which are rich in adipocytes and fatty acids. Given reasons including complex TME, the clinical efficacy of new immunotherapies such as immune checkpoint blockade (ICB) therapy for OvCa is very limited. Therefore, treatment regimens based on new mechanisms are urgently needed to be developed. In this study, we applied the Gene Expression Omnibus (GEO) database, clinical specimens, cell lines, and mouse models to investigate whether reprogramming the fatty acid metabolism in B cells could enhance their APC function and to explore the underlying mechanisms. We also evaluated the therapeutic effects of the combined treatment using APC-enhanced-B cells adoption with low-dose chemotherapy in metastatic OvCa mice. Our research provides new clues forB cells-based anti-tumor immunotherapy.
A phase I, single-arm, open-label, dose-escalation, multicenter study of SAR445419, an off-the-shelf, ex vivo expanded allogeneic natural killer cell product, in participants with relapsed or refractory acute myeloid leukemia.
Konopleva M, Bhatt VR, Mantzaris I … +13 more , Maiti A, Gundabolu K, Schafer J, Jensen K, Saleem R, Li Y, Drewniak A, Bay P, Huh W, Yildirim O, Abbadessa G, Cooley S, Daver N
Cancer Immunol Immunother · 2026 Apr · PMID 41963545 · Full text
BACKGROUND: SAR445419 is an investigational, off-the-shelf, allogeneic NK cell therapy derived from donor peripheral blood mononuclear cells and expanded ex vivo using PM21 particles. METHODS: This multicenter, Phase 1,...
BACKGROUND: SAR445419 is an investigational, off-the-shelf, allogeneic NK cell therapy derived from donor peripheral blood mononuclear cells and expanded ex vivo using PM21 particles. METHODS: This multicenter, Phase 1, dose-escalation study (NCT05712278) evaluated optimal dose(s), safety, and tolerability of SAR445419 in adults (aged ≥ 18 years) with relapsed/refractory acute myeloid leukemia (R/R AML). Following lymphodepleting chemotherapy (fludarabine 30 mg/m/day and cytarabine 2 g/m/day for 5 days), participants received six intravenous SAR445419 (1 × 10 and 3 × 10 NK cells/dose) doses, starting with the lower dose. The primary endpoint was the incidence of dose-limiting toxicities (DLTs), and key secondary endpoints included adverse events (AEs), hematological recovery, hematopoietic stem cell transplantation, and response rate. RESULTS: Of the 12 planned participants, 7 patients were enrolled, of whom 6 received SAR445419 before sponsor decided early study termination for reasons unrelated to safety or efficacy. No DLTs were observed. All participants experienced treatment-emergent adverse events (TEAEs); six had grade ≥ 3 TEAEs; and four had serious adverse events (SAEs). Two SAR445419-related SAEs (infusion-related reactions: both grade 2) were managed with supportive care. All participants experienced grade 3 anemia and grade 4 thrombocytopenia and neutropenia. Five deaths were reported, all due to disease progression, none related to SAR445419. No clinical responses were observed. CONCLUSIONS: This study demonstrated the overall safety of off-the-shelf ex vivo expanded allogeneic NK cells in patients with R/R AML. The successful manufacturing and distribution support the feasibility of donor-derived off-the-shelf NK cells in a clinical setting. Further investigations are required to improve the clinical efficiency of NK cells.
Comparative safety of PD-1 and PD-L1 inhibitors in advanced solid tumors: a real-world cohort study with competing risk analysis.
Shih YH, Wang SJ, Fan CT … +6 more , Lu TF, Chen YF, Sun L, Hsu ST, Tseng JJ, Lu CH
Cancer Immunol Immunother · 2026 Apr · PMID 41961286 · Full text
BACKGROUND: Real-world evidence comparing long-term safety between PD-1 and PD-L1 inhibitors is limited, and the impact of competing mortality is unclear. METHODS: This retrospective cohort study utilized the TriNetX pla...
BACKGROUND: Real-world evidence comparing long-term safety between PD-1 and PD-L1 inhibitors is limited, and the impact of competing mortality is unclear. METHODS: This retrospective cohort study utilized the TriNetX platform (2014-2024). Adults with advanced solid tumors initiating a PD-1 or PD-L1 inhibitor within 3 months of diagnosis were included. A 1:1 propensity score match created balanced cohorts. The primary outcome was the 1-year incidence of immune-related adverse events (irAEs). Standard Cox models and Fine-Gray competing risk models (accounting for death) were used to estimate hazard ratios (HRs) and subdistribution hazard ratios (sHRs), respectively. RESULTS: After matching, 22,672 patients (11,336 per group) were analyzed. In standard Cox analysis, PD-L1 inhibitors were associated with a lower risk of skin rash (HR 0.66, 95% CI 0.56-0.78), colitis (HR 0.79, 0.71-0.87), and nephritis (HR 0.71, 0.54-0.94) compared to PD-1 inhibitors. The competing risk analysis revealed that all-cause mortality was the overwhelmingly dominant outcome. Consequently, PD-L1 inhibitor use was associated with uniformly lower sHRs for every irAE analyzed (range: 0.85-0.88), with the sHR for mortality itself at 0.88 (0.84-0.92). This pattern, indicating the safety signal was heavily confounded by survival, was consistent across sex and age subgroups but more pronounced in males and older patients. CONCLUSION: PD-L1 inhibitors are associated with a lower risk of specific irAEs. However, mortality is the dominant competing risk in advanced cancer, fundamentally shaping safety assessments. Real-world studies must account for competing mortality to avoid distorted conclusions.
Targeting the COX-2/PGE axis to enhance NK and T cell immunotherapy in brain tumors.
Shen CJ, Florentino-Krasnov J, Liao YC … +4 more , Tang HW, Nainggolan BWM, Chiang YH, Hsu TI
Cancer Immunol Immunother · 2026 Apr · PMID 41961113 · Full text
Aggressive brain tumors such as glioblastoma (GBM) remain among the most lethal human cancers, with a median survival of only 15 months despite multimodal treatment. Their resistance arises from a triad of barriers-the b...
Aggressive brain tumors such as glioblastoma (GBM) remain among the most lethal human cancers, with a median survival of only 15 months despite multimodal treatment. Their resistance arises from a triad of barriers-the blood-brain barrier (BBB), marked intratumoral heterogeneity, and a profoundly immunosuppressive tumor microenvironment (TME). Immunotherapeutic strategies based on natural killer (NK) and T cells, leveraging antigen-independent cytotoxicity and antigen-specific precision, respectively, offer potential breakthroughs but are often limited by chronic neuroinflammation. A key driver of TME suppression is prostaglandin E2 (PGE2), produced via the cyclooxygenase-2 (COX-2) pathway. PGE2 exerts a dual role: Intracellularly, it can promote apoptosis, whereas extracellularly, it fosters tumor progression, immune evasion, and therapeutic resistance. Through activation of EP2 and EP4 receptors, PGE2 signals via Gαs proteins to elevate cyclic adenosine monophosphate (cAMP), leading to impaired cytotoxic immunity. This signaling downregulates NK cell activating receptors (e.g., NKG2D, NKp30), induces CD8⁺ T cell exhaustion, and promotes regulatory T cell expansion. The COX-2/PGE₂ axis further mediates resistance to checkpoint inhibitors, CAR-T therapy, and chemotherapy by enhancing neuronal excitation through EP1 receptor activation in GBM. Targeting this pathway has therefore emerged as a compelling therapeutic strategy, which can restore NK and T cell function and sensitize tumors to immunotherapy. Combining PGE₂ modulation with next-generation NK/T cell approaches-including CAR-NK and CAR-T platforms-holds promise to overcome immune resistance and redefine therapeutic paradigms for GBM and other central nervous system malignancies.
Targeting ST3GAL1 to downregulate ligands for the glycoimmune checkpoint Siglec-7 and reverse immune escape in hepatocellular carcinoma.
Fan TC, Hung TH, Yeh CT … +6 more , Lin PT, Chang NC, Lo TC, Wu TJ, Yu J, Yu AL
Cancer Immunol Immunother · 2026 Apr · PMID 41961075 · Full text
Sorafenib is the first-line therapy for advanced hepatocellular carcinoma (HCC). However, acquired resistance to sorafenib remains a significant challenge. Previous studies have shown that sorafenib treatment induces the...
Sorafenib is the first-line therapy for advanced hepatocellular carcinoma (HCC). However, acquired resistance to sorafenib remains a significant challenge. Previous studies have shown that sorafenib treatment induces the formation of truncated O-glycans in HCC cells, but the relationship between sorafenib-induced glycosylation changes and acquired therapy resistance remains unclear. Primary natural killer (NK) cells, freshly isolated from peripheral blood or following culture and expansion, expressed the glycoimmune checkpoints Siglec-7 and Siglec-9. HCC cells exhibited varying levels of Siglec-7/9 ligands on their surface. Sorafenib-resistant liver cancer cells displayed hypersialylation, leading to increased expression of surface Siglec-7/9 ligands, which conferred protection against NK cell-mediated cytotoxicity. Silencing ST3GAL1 significantly reduced Siglec-7 ligand expression on liver cancer cells, enhancing their susceptibility to NK-mediated cytotoxicity and cetuximab-induced antibody-dependent cellular cytotoxicity (ADCC) in epidermal growth factor receptor (EGFR)-expressing tumor cells. Furthermore, high ST3GAL1 expression correlated with poor clinical outcomes in patients with stage 1-2 HCC. This study highlights the critical role of ST3GAL1 in regulating Siglec-7 ligands to facilitate immune escape from NK cell cytotoxicity. Moreover, its elevated expression is associated with adverse clinical outcomes in HCC. Targeting ST3GAL1 may represent a promising strategy to enhance NK cell-mediated anti-tumor immunity in HCC.
Correction to: GPX4 is a key ferroptosis regulator orchestrating T cells and CAR-T-cells sensitivity to ferroptosis.
Kłopotowska M, Baranowska I, Hajduk S … +12 more , Jurga A, Leśniowska N, Łaźniewski M, Granica M, Krawczyk M, Dziewicka M, Graczyk A, Słupski J, Zagożdżon R, Plewczynski D, Winiarska M, Bajor M
Cancer Immunol Immunother · 2026 Apr · PMID 41944919 · Full text
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Correction: Comparison of real-world efficacy and safety of nivolumab plus ipilimumab or pembrolizumab combined with platinum-based chemotherapy as first-line treatment for advanced non-small cell lung cancer in a German population.
Weber M, von Hammerstein-Equord AF, Weinreich M … +2 more , Andreas S, Rittmeyer A
Cancer Immunol Immunother · 2026 Apr · PMID 41942614 · Full text
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Impact of immunochemotherapy administration sequence on overall survival in advanced esophageal and gastric cancers: a propensity score-matched multicenter analysis.
Hang J, Wu L, Xiao L … +10 more , Duan Q, Zhao H, Huang J, Guo J, Huang Y, Zhang D, Cheng G, Dong X, Xue P, Chang J
Cancer Immunol Immunother · 2026 Apr · PMID 41941004 · Full text
BACKGROUND: The optimal sequence of administering immune checkpoint inhibitors (ICIs) and chemotherapy in advanced esophageal cancer (EC) and gastric cancer (GC) remains to be established. Understanding how this sequenci...
BACKGROUND: The optimal sequence of administering immune checkpoint inhibitors (ICIs) and chemotherapy in advanced esophageal cancer (EC) and gastric cancer (GC) remains to be established. Understanding how this sequencing affects overall survival (OS) is crucial for optimizing treatment strategies. METHODS: This multicenter study enrolled 334 patients diagnosed with advanced EC or GC between January 2018 and October 2024. To reduce confounding biases, propensity score matching (PSM) was applied, resulting in 292 matched patients categorized into two groups, including those receiving ICIs first (IF) and those receiving chemotherapy first (CF). RESULTS: Following PSM, Kaplan-Meier analysis showed that the CF group had a significantly prolonged median OS compared to the IF group (16.80 vs. 14.60 months; p = 0.014). These findings were further corroborated in the unmatched cohort (16.60 vs. 14.60 months; p = 0.012). Multivariable analysis identified ECOG performance status, PD-L1 expression, antibiotic use, and line of ICI treatment as independent prognostic factors, whereas the immunochemotherapy administration sequence did not retain independent prognostic significance. Subgroup analysis revealed that among patients receiving first-line immunochemotherapy, those in the CF group had significantly longer OS (16.50 vs. 12.30 months; p = 0.004), with no significant difference observed for those beyond first-line treatment (p = 0.862). The objective response rate and disease control rate were comparable between the two groups. CONCLUSIONS: This study suggests that administering chemotherapy prior to immunotherapy appears to improve OS in patients with advanced EC and GC, particularly when initiated as first-line treatment. These findings highlight the need for further research into biomarkers and personalized treatment strategies to enhance patient outcomes.
Hypoalbuminemia induces immunosuppression through disorder in macrophages and drives resistance to immune checkpoint inhibitors.
Yang F, Long Y, Li Y … +7 more , Bai Y, Liu Y, Cheng D, Li T, Lu Y, Han X, Hu Y
Cancer Immunol Immunother · 2026 Apr · PMID 41940988 · Full text
Hypoalbuminemia is a common clinical biomarker associated with poor outcomes in cancer patients. While it correlates with resistance to immune checkpoint inhibitors (ICIs), the direct functional role and underlying mecha...
Hypoalbuminemia is a common clinical biomarker associated with poor outcomes in cancer patients. While it correlates with resistance to immune checkpoint inhibitors (ICIs), the direct functional role and underlying mechanisms in driving immunotherapy resistance remain unclear. In our study, we demonstrated that hypoalbuminemia directly drives ICIs resistance by orchestrating an immunosuppressive tumor microenvironment (TME) through impaired macrophage arginine metabolism. In a C57/BL model, low-protein diet-induced hypoalbuminemia mice bearing LLC tumors showed poor response to immunotherapy. Comprehensive immune profiling revealed a suppressed TME, characterized by reduced CD8 T cell infiltration and increased macrophage abundance. Depletion of tumor-associated macrophages (TAMs) alleviated this immunosuppression. Transcriptomic analysis of TAMs from low-protein diet-induced hypoalbuminemia mice revealed a significant downregulation of the arginine biosynthesis pathway, which was consistent with observed reductions in systemic arginine levels. Crucially, dietary arginine supplementation successfully reversed the immunosuppressive phenotype and restored ICIs efficacy. However, this restorative effect of arginine is significantly dependent on its action on macrophages. Our findings establish low-protein diet-induced hypoalbuminemia as a key driver of immunotherapy resistance, unveil a novel metabolic-immune circuit centered on TAM arginine metabolism, and identify arginine replenishment as a potential therapeutic strategy to reverse immune suppression in hypoalbuminemia patients.
Compartment-specific GLUT1 patterns in colorectal liver metastases: invasive-margin GLUT1 associates with outcome in solitary disease.
Grießhammer E, Bogovic N, Geissler EK … +6 more , Evert K, Götz M, Hackl C, Fichtner-Feigl S, Schlitt HJ, Brunner SM
Cancer Immunol Immunother · 2026 Apr · PMID 41940986 · Full text
BACKGROUND: Colorectal liver metastases (CRLM) are a major cause of cancer-related deaths. Glucose transporter 1 (GLUT1) is a key mediator of glycolytic metabolism in malignant and immune cells; however, the prognostic r...
BACKGROUND: Colorectal liver metastases (CRLM) are a major cause of cancer-related deaths. Glucose transporter 1 (GLUT1) is a key mediator of glycolytic metabolism in malignant and immune cells; however, the prognostic relevance of compartment-specific GLUT1 patterns in CRLM remains undefined. We hypothesized that spatial GLUT1 expression at the tumor-liver interface may reflect clinically relevant microenvironmental biology. METHODS: We retrospectively analyzed data of 192 patients who underwent curative-intent resection for CRLM (75 solitary; 117 multiple). GLUT1 expression was assessed by immunohistochemistry in the tumor tissue (Tu) and infiltration margin (Im) and was correlated with overall survival using Cox regression. Double immunofluorescence for CD8 and GLUT1 was performed for qualitative visualization at the infiltration margin. In an exploratory subset (n = 5), flow cytometry and in vitro killing assays were conducted on GLUT1⁺ versus GLUT1⁻ CD8⁺ tumor-infiltrating lymphocytes (TILs). RESULTS: Tumoral GLUT1 correlated with Ki67 (Spearman's ρ = 0.31, p = 0.003) but was not independently associated with overall survival in the main cohort (multivariable HR 1.183, 95% CI 0.74-1.90; p = 0.485). In the main cohort, capsule presence remained strongly associated with improved survival (HR 0.35, 95% CI 0.21-0.58; p < 0.001). In contrast, high invasive-margin GLUT1 was independently associated with improved survival in the predefined solitary cohort (HR 0.379, 95% CI 0.18-0.81; p = 0.012). Double immunofluorescence demonstrated the qualitative co-localization of the GLUT1 signal with CD8⁺ cells at the infiltration margin. In exploratory assays (n = 5), flow cytometry suggested GLUT1 enrichment in CD8⁺ terminally differentiated effector memory T cells re-expressing CD45RA (TEMRA), and GLUT1⁺ TIL fractions showed higher in vitro tumor cell killing compared with GLUT1⁻ cells. CONCLUSION: GLUT1 shows compartment- and context-dependent associations in the CRLM. While tumor-core GLUT1 is linked to proliferative activity, invasive-margin GLUT1 is associated with favorable outcomes in solitary metastases. Immunofluorescence and functional data provide hypothesis-generating context and warrant validation with quantitative spatial immune profiling and independent cohorts.
Repurposing rosmarinic acid as an anti-colorectal cancer agent through bolstering T cell anti-tumor immunity by enhancing activation of MEK1-mediated TCR signaling.
Kang Z, Li X, Ma X … +2 more , Yan F, Wang Z
Cancer Immunol Immunother · 2026 Apr · PMID 41925912 · Full text
Activation of the T cell receptor (TCR) complex is fundamental to initiating adaptive immune responses, particularly in CD8⁺ cytotoxic T lymphocytes that mediate anti-tumor immunity. However, the immunosuppressive tumor...
Activation of the T cell receptor (TCR) complex is fundamental to initiating adaptive immune responses, particularly in CD8⁺ cytotoxic T lymphocytes that mediate anti-tumor immunity. However, the immunosuppressive tumor microenvironment often impairs TCR signaling, limiting the efficacy of T cell-based cancer immunotherapies. Here, we report the identification of rosmarinic acid (RA), a naturally occurring polyphenolic compound, as a potent small molecule enhancer of TCR signaling. RA significantly augments IL-2 and IFN-γ production, promotes T cell proliferation, and enhances cytotoxicity of CD8⁺ T cells in vitro. Mechanistically, RA directly binds to MEK1, a key kinase in the MAPK/ERK pathway, with high affinity, leading to reduced MEK1 phosphorylation and downstream signaling activation. Transcriptomic and metabolic profiling of RA-treated CD8⁺ T cells revealed upregulation of genes associated with TCR signaling, calcium flux, PPAR signaling, and oxidative phosphorylation, indicating a broad remodeling of T cell effector function and metabolism. In vivo, RA treatment significantly suppressed tumor growth, increased tumor-infiltrating lymphocyte (TIL) frequency, and improved survival in MC38 tumor-bearing mice. These effects were abrogated upon CD8⁺ T cell depletion, confirming their central role. Furthermore, RA synergized with anti-PD-1 therapy and enhanced the efficacy of adoptively transferred OT-I T cells in colorectal tumor-bearing hosts. Collectively, our findings reveal RA as a novel immunomodulatory agent that boosts CD8⁺ T cell responses via MEK1-mediated TCR signaling enhancement, providing a promising strategy for drug repurposing in cancer immunotherapy.
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