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The clinical efficacy of immune checkpoint inhibitors (ICIs) in colorectal cancer (CRC) remains limited. Modulation of the glucagon-like peptide-1 receptor (GLP-1R) may enhance T-cell-mediated antitumor responses. The present study aimed to evaluate the antitumor effects of the GLP-1R antagonist Exendin 9–39 (Exe-9) combined with anti-programmed cell death protein-1 (PD-1) treatment in preclinical CRC models. Using in vitro co-culture assays, ELISA and in vivo murine models, alongside immunohistochemical and molecular analyses of clinical samples, HT-29 and MC38-OVA colon cancer cell lines were co-cultured in vitro with activated T cells in the presence of Exe-9. In vivo, male BALB/c mice were injected with MC38 to establish a CRC model and nude mice were used to assess T-cell dependency. To evaluate this synergistic effect, BALB/c mice with CRC were treated with Exe-9, anti-PD-1 or a combination. Additionally, clinical CRC samples were analyzed to assess the association of GLP-1R expression with the immunotherapy response. Exe-9 significantly enhanced T-cell-mediated cytotoxicity in CRC cell lines and reduced tumor growth in immunocompetent CRC mice; however, this effect was not observed in nude mice. Furthermore, combination therapy with the GLP-1R antagonist and anti-PD-1 yielded an improved antitumor effect compared with either treatment alone, and high GLP-1R ex2pression in clinical samples correlated with poor ICI response. These findings suggest that GLP-1R antagonism potentiates T-cell-mediated antitumor immunity and may provide a promising adjunctive therapeutic strategy for patients with CRC when combined with ICIs in the future.

Immune checkpoint blockers (ICBs) have demonstrated substantial efficacy across various malignancies, yet the benefits of ICBs are limited to a subset of patients. Therefore, it is essential to identify novel therapeutic targets. By integrating multi-omics data from cohorts of patients with melanoma treated with ICBs, a positive correlation is observed between tumor CD137L expression and the efficacy of PD-1 blockade. Functionally, CD137L induction in cancer cells significantly enhances anti-tumor immunity by promoting CD8 + T cell survival, both in vivo and in vitro. Mechanistically, helicase-like transcription factor (HLTF) is identified as a pivotal transcriptional regulator of CD137L , controlling its expression through phosphorylation of serine at position 398. Therapeutically, the AMPK agonist AICAR (acadesine) as an inducer of CD137L , exhibiting synergistic effects with PD-1 or CTLA-4 blockade. In summary, our findings elucidate a mechanism controlling CD137L expression and highlight a promising combination therapy to enhance the efficacy of ICBs in melanoma. One Sentence Summary: Inducing co-stimulatory immune checkpoint CD137L expression in melanoma cells enhances T cell-mediated anti-tumor immunity. Subject terms: Tumour immunology, Cancer immunotherapy

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the lack of ER, PR, and HER2 expression. Its aggressive behavior, high degree of tumor heterogeneity, and immunosuppressive tumor microenvironment (TME) are associated with poor clinical outcomes, rapid disease progression, and limited therapeutic options. Although chimeric antigen receptor (CAR)-engineered T cell therapy has shown certain promise, its applicability in TNBC is hindered by antigen escape, TME-mediated suppression, and the logistical constraints of autologous cell production. In this study, we employed hematopoietic stem and progenitor cell (HSPC) gene engineering and a feeder-free HSPC differentiation culture to generate allogeneic IL-15-enhanced, mesothelin-specific CAR-engineered invariant natural killer T ( Allo15 MCAR-NKT) cells. These cells demonstrated robust and multifaceted antitumor activity against TNBC, mediated by CAR- and NK receptor-dependent cytotoxicity, as well as selective targeting of CD1d + TME immunosuppressive cells through their TCR. In both orthotopic and metastatic TNBC xenograft models, Allo15 MCAR-NKT cells demonstrated potent antitumor activity, associated with robust effector and cytotoxic phenotypes, low exhaustion, and a favorable safety profile without inducing graft-versus-host disease. Together, these results support Allo15 MCAR-NKT cells as a next-generation, off-the-shelf immunotherapy with strong therapeutic potential for TNBC, particularly in the context of metastasis, immune evasion, and treatment resistance. The online version contains supplementary material available at 10.1186/s13045-025-01736-9.