May 15, 2026 — The research group led by Professor Zemin Zhang at the Peking University Biomedical Pioneering Innovation Center (BIOPIC) has published a research article entitled “Targeting LRRC15 in Cancer-Associated Fibroblasts Modifies the Extracellular Matrix and Enhances Tumor Immune Responses to Suppress Lung Cancer Progression” online in Cancer Research. This study systematically reveals the critical role of the CAF-specific molecule LRRC15 in lung cancer progression and proposes a novel therapeutic strategy that targets cancer-associated fibroblasts (CAFs) to remodel the tumor microenvironment and enhance antitumor immunity.

Lung cancer is one of the most prevalent and lethal malignancies worldwide, posing an especially severe burden in China. Non–small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases. Despite continuous advances in early diagnosis and treatment, therapeutic outcomes for patients with advanced lung cancer remain limited. In recent years, immune checkpoint inhibitors have shown remarkable efficacy in a subset of patients; however, their applicability is restricted, and therapeutic resistance remains a major challenge, underscoring the urgent need to develop new immunotherapeutic strategies.

Accumulating evidence indicates that tumor initiation and progression are not solely determined by cancer cells themselves but are profoundly influenced by diverse non-malignant components within the tumor microenvironment (TME). Among these, cancer-associated fibroblasts (CAFs) represent a key stromal population that extensively interacts with tumor cells, immune cells, and extracellular matrix components, playing critical roles in tumor-associated immunosuppression and disease progression.

In this study, the authors integrated multiple public single-cell transcriptomic datasets to construct a comprehensive single-cell atlas of stromal cells in lung cancer, enabling a systematic characterization of fibroblast heterogeneity within the TME. They identified a tumor-enriched CAF subset marked by LRRC15 expression (LRRC15⁺ CAFs), whose increased abundance in lung cancer tissues was significantly associated with poor patient prognosis.

Further screening for potential therapeutic targets within LRRC15⁺ CAFs revealed that LRRC15 is highly and specifically expressed in this CAF subset at tumor sites and closely correlates with lung cancer progression, suggesting that LRRC15 is a key functional molecule and a promising therapeutic target.

Using multiple mouse lung cancer models, the research team demonstrated that loss of LRRC15 in CAFs markedly suppressed tumor progression in an immune-dependent manner. Mechanistic studies revealed that LRRC15 promotes macrophage polarization toward an immunosuppressive M2 phenotype, thereby inhibiting CD8⁺ T cell–mediated antitumor immunity.

At the mechanistic level, both human- and mouse-derived LRRC15⁺ CAFs exhibited significant enrichment of extracellular matrix (ECM)–related signaling pathways. In contrast, LRRC15 deficiency markedly reduced ECM-associated gene expression and collagen production in CAFs. In vitro experiments further showed that LRRC15 enhances ECM deposition—particularly type I collagen production—in CAFs, which in turn drives macrophage M2 polarization.

Figure 1. LRRC15 expression in CAFs mediates macrophage M2 polarization, thereby promoting lung cancer progression.

Based on these findings, the authors developed a bispecific LRRC15–TGF-β trap antibody that selectively restricts TGF-β blockade to LRRC15⁺ CAFs within the tumor microenvironment, thereby minimizing the systemic toxicity associated with global TGF-β inhibition. In the KPS lung cancer model, this bispecific antibody significantly delayed tumor growth and markedly alleviated splenomegaly in treated mice, demonstrating favorable safety and therapeutic potential. Collectively, this study provides a novel stromal-targeted strategy for lung cancer treatment and highlights LRRC15 as a promising immunomodulatory target within CAFs.

Figure 2. LRRC15 promotes extracellular matrix (ECM) production in CAFs, driving macrophage M2 polarization and suppressing CD8⁺ T cell cytotoxic activity.

Academician Zemin Zhang (BIOPIC, Peking University/Chongqing Medical University) and Associated Investigator Linnan Zhu (BIOPIC, Peking University/Chongqing Medical University) are co-corresponding authors. Dr. Lu Qi, PhD student Guohui Dang, and PhD student Xinnan Ling are co-first authors. This research was supported by funding from the National Key Research and Development Program of China, Start-up Grant for Recruited Scholars of Chongqing Medical University, National Natural Science Foundation of China and Changping Laboratory.

Paper link: https://aacrjournals.org/cancerres/article/doi/10.1158/0008-5472.CAN-25-2871/771990