Targeting LRRC15 in Cancer-Associated Fibroblasts Modifies the Extracellular Matrix and Enhances Tumor Immune Responses to Suppress Lung Cancer Progression.

Cancer-associated fibroblasts (CAF) play a crucial role in shaping the tumor microenvironment and driving tumor progression. Although single-cell transcriptomics has revealed the phenotypic and functional heterogeneity of CAFs, effective therapeutic strategies targeting CAFs remain urgently needed. In this study, we identified LRRC15+ CAFs as a tumor-specific CAF subset in lung cancer and proposed LRRC15 as a potential therapeutic target. LRRC15 deficiency suppressed lung cancer progression in mice by modulating macrophage polarization and enhancing CD8+ T-cell activation. Mechanistically, LRRC15 deficiency inhibited CD206+ macrophage polarization by reducing extracellular matrix (ECM) production in CAFs, leading to increased CD8+ T-cell cytotoxicity. Finally, development of a bispecific antibody targeting LRRC15 and TGFβ enabled effective downregulation of LRRC15 expression in CAFs and limited tumor progression in mice. This study highlights LRRC15 as a promising therapeutic target and provides insights into CAF-directed cancer treatment strategies. SIGNIFICANCE: LRRC15 in cancer-associated fibroblasts enhances extracellular matrix deposition, facilitates M2 macrophage polarization, and suppresses CD8+ T cell-mediated immunity, thereby promoting lung cancer progression and representing a potential therapeutic target.