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

Abstract

Cancer-associated fibroblasts (CAFs) play a crucial role in shaping the tumor microenvironment (TME) and driving tumor progression. While single-cell transcriptomics has revealed the phenotypic and functional heterogeneity of CAFs, effective therapeutic strategies targeting CAFs remain urgently needed. Here, 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 TGF-β 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.