CD248 induces PD-L1 expression on cancer-associated fibroblasts to promote NSCLC immune escape

Zeyang Yang¹Xuanyin Wang¹Xu Zhu²Long Li²Zeng Xian Lin¹Jiaming Ren¹Lu Wang¹Jiangwei Wu¹Qiaoling Zhang¹Siyu Wang¹Maoqin Lu¹Juan Zhai¹Xinlei Liu²Jing Xiao¹Tao Jin¹Ying Zhang¹Yun Wang¹Jian Zhang²Zhu Zeng¹Jieheng Wu^1*

• ¹Guizhou Medical University, Guiyang, China
• ²The Affiliated Hospital of Guizhou Medical University, Guiyang, China

Tumor immune escape is a pivotal mechanism in tumor progression. Within the tumor microenvironment (TME), cancer-associated fibroblasts (CAFs) contribute to this process by expressing high levels of PD-L1, which impairs the activity of CD8⁺T cells. While CD248 has been proposed as a marker for CAFs in non-small cell lung cancer (NSCLC), its role in immune escape has remained unclear. This study shows CD248 enhances PD-L1 expression in CAFs, suppressing CD8⁺ T-cell function and facilitating NSCLC cell invasion and migration. Mechanistically, CD248 activates the FAK/Src/JNK/c-Jun signaling cascade, which drives PD-L1 upregulation in CAFs. In vivo, lung tumors in fibroblast-specific CD248 knockout mice exhibited significantly reduced growth, accompanied by increased granzyme B⁺CD8⁺T cell infiltration, compared to wild-type controls. Therapeutic response to tislelizumab was also improved in CD248-deficient mice. These findings reveal that CD248 promotes immune escape in NSCLC by inducing PD-L1 expression in CAFs via the FAK/Src/JNK/c-Jun pathway, highlighting CD248 as a potential therapeutic target to enhance immunotherapy efficacy.