Claudin-7 deficiency induces metabolic reprogramming of neutrophils in the colorectal cancer microenvironment.

Neutrophils are integral components of the bone marrow and stromal cell network. They express the immune checkpoint molecule PD-L1 and can induce T cell exhaustion, thereby promoting immunosuppression. In this study, we investigated whether tumor-derived Cldn7 deficiency could recruit polymorphonuclear neutrophils (PMNs), induce their metabolic reprogramming, and consequently drive their transition toward a pro-tumor phenotype, leading to the establishment of an immunosuppressive tumor microenvironment (TME). Using single-cell RNA sequencing, clinical sample validation, and both in vivo and in vitro experiments, we found that Cldn7 deficiency in colorectal cancer (CRC) results in a tumor microenvironment characterized by significantly increased infiltration of CD11b⁺ Ly6G⁺ neutrophils. This is accompanied by neutrophil metabolic reprogramming that facilitates their phenotypic shift toward a tumor-promoting state, which in turn suppresses the cytotoxic function of CD8⁺ T cells and contributes to the formation of an immunosuppressive TME, thereby accelerating CRC progression. Mechanistically, Cldn7 deficiency indirectly activates the NF-κB signaling pathway, leading to elevated secretion of chemokines such as CXCL1 that are responsible for PMN recruitment. Inhibition of the NF-κB/CXCL1 axis reduces PMN infiltration, decreases PD-L1 expression on neutrophils, suppresses neutrophil glycolysis and histone lactylation, reverses the exhausted phenotype of CD8⁺ T cells, thereby mitigating the immunosuppressive microenvironment. Furthermore, overexpression of Cldn7 enhances the efficacy of immune checkpoint blockade (ICB) therapy.Collectively, our findings indicate that Cldn7 deficiency not only contributes to immune evasion and malignant progression in CRC but also plays a critical role in immune modulation. Targeting PMN metabolic reprogramming and immunosuppressive function associated with Cldn7 loss may offer a promising strategy to improve the therapeutic efficacy of immunotherapy in CRC.