NMB+ CXCL13+ CD4+ T cells -derived neuromedin-B promotes neuropeptide S receptor 1 positive malignant cells senescence and malignancy

Colorectal cancer (CRC) with liver metastases (CRCLM) remains a clinical challenge. CXCL13 is widely recognized as a biomarker of immunotherapy response. However, the functional heterogeneity (protumor vs. antitumor) of CXCL13⁺CD4⁺ T cell subsets has long been controversial. Through integrated analysis of single-cell RNA sequencing data from CRC clinical samples and pan-cancer datasets, combined with experimental validations, we first identified a pro-metastatic NMB⁺CXCL13⁺CD4⁺ T cell subset and uncovered a mechanism by which this subset regulates tumor cell "senescence-malignant transition", the NMB-NPSR1 axis. These NMB⁺CXCL13⁺CD4⁺ T cells induced senescence in NPSR1⁺ malignant cells via NMB secretion, leading to enhanced invasiveness and migration despite reduced proliferation. Activation of NPSR1 triggered the Wnt signaling pathway and Epithelial-Mesenchymal Transition (EMT), thereby enhancing cellular malignancy. This NPSR1+ senescent subpopulation also recruited endothelial cells and disrupted tight junction integrity, fostering a pro-metastatic microenvironment. As a proof-of-principle study, combination of the NPSR1 inhibitor SHA68 and anti-PD1 demonstrated remarkable antitumor effects using mouse models of CRC metastasis. Overall, this study uncovered the role of NMB+ CXCL13+ CD4+ T cells in promoting tumor cell senescence while influencing tumor metastasis, offering potential clinical implications for the diagnosis and treatment of metastatic CRC.