NMB+CXCL13+CD4+ T Cell-Derived Neuromedin B Promotes Neuropeptide S Receptor 1-Positive Malignant Cell Senescence and Malignancy

Colorectal cancer with liver metastases 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 colorectal cancer clinical samples and pan-cancer datasets, combined with experimental validations, we first identified a prometastatic neuromedin B+ (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, thereby enhancing cellular malignancy. This NPSR1+ senescent subpopulation also recruited endothelial cells and disrupted tight junction integrity, fostering a prometastatic microenvironment. As a proof-of-principle study, the combination of the NPSR1 inhibitor SHA68 and anti-PD-1 demonstrated remarkable antitumor effects using mouse models of colorectal cancer 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 colorectal cancer.