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

ABSTRACT 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.