Interferon-γ-stimulated antigen-presenting cancer-associated fibroblasts hinder neoadjuvant chemoimmunotherapy efficacy in lung cancer.

Conventional neoadjuvant chemotherapy provides limited benefit for patients with resectable non-small cell lung cancer (NSCLC). Recently, neoadjuvant chemoimmunotherapy (NCIT) has transformed the perioperative management of NSCLC by priming systemic anti-tumor immunity before surgery, yet it remains ineffective for at least 50% of patients. Through single-cell sequencing analysis of our NCIT cohort, we identify that antigen-presenting cancer-associated fibroblasts (apCAFs) can impede the efficacy of NCIT. Using a custom cancer-associated fibroblast biobank, we uncover that interferon (IFN)-γ stimulates apCAF expansion via the JAK1/2-STAT1-IFI6/27 pathway. Mechanistically, apCAFs significantly contribute to PD-L2 expression in the tumor microenvironment (TME), triggering the accumulation of FOXP1regulatory T cells (Tregs) through the PD-L2-RGMB axis. Reprogramming apCAFs by inhibiting the IFN-γ pathway or blocking the PD-L2-RGMB axis substantially mitigates apCAFs-mediated FOXP1Tregs' expansion. In summary, we reveal the role of apCAFs in compromising NCIT efficacy and propose applications for anti-PD-L2/RGMB regimens to synergize with anti-PD1 therapies by targeting apCAFs.