March 3, 2026Open Access

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

Key Points

LRRC15 deficiency suppresses lung cancer progression by modifying immune responses and matrix production.
Enhanced CD8+ T cell activation was observed with LRRC15 targeting, leading to reduced tumor growth.
Inhibition of CD206+ macrophage polarization occurs due to decreased extracellular matrix in cancer-associated fibroblasts.
This highlights the potential of LRRC15 as a therapeutic target for improving lung cancer treatment.

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.

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

Key Points

Abstract

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