PD‐1 Inhibits CD4+ TRM‐Mediated cDC1 Mobilization via Suppressing JAML in Human NSCLC

Tissue-resident memory CD4+ T cells (CD4+ TRMs) are pivotal in immune responses during inflammation and infection, yet their phenotype and function within the tumor microenvironment (TME) remain elusive. Here, we delineated CD4+ TRMs in non-small cell lung cancer (NSCLC) using CD103 and CD69 as defining markers and demonstrated that their transcriptional and phenotypic profiles closely resembled those observed in murine models. Tumor-infiltrating CD4+ TRMs exert helper antitumor effects by secreting the chemokine XCL1 to recruit conventional type 1 dendritic cells (cDC1s), facilitating antigen presentation and priming cytotoxic T lymphocyte responses. Mechanistically, we identified the costimulatory molecule JAML as essential for CD4+ TRM-mediated cDC1 mobilization. Compared with their counterparts in normal lung tissue, tumor-infiltrating CD4+ TRMs exhibited elevated expression of immune checkpoint molecules, indicating a dysfunctional state, accompanied by significantly reduced XCL1 expression. PD-1 signaling within the NSCLC TME suppressed JAML expression-an effect reversible by PD-1 blockade-while the administration of a JAML agonist further enhanced the antitumor efficacy of PD-1 inhibitors in tumor-bearing mice. Clinically, the presence of XCL1-secreting CD4+ TRMs positively correlated with favorable clinical outcomes and enhanced responses to anti-PD-1 immunotherapy in NSCLC patients. Our findings reveal a critical role for JAML in facilitating CD4+ TRM-mediated cDC1 mobilization within the NSCLC TME and highlight the translational potential of targeting CD4+ TRMs to enhance the efficacy of immune checkpoint blockade therapies.