Targeting HMGB1 modulates cancer-associated fibroblasts and enhances radiotherapy in lung adenocarcinoma.

Radio-resistance remains a major challenge in the effective treatment of lung cancer. Cancer-associated fibroblasts (CAFs), the predominant cellular components in solid tumors, play a crucial role in tumor treatment and resistance. Thus, understanding the interactions between CAFs and tumor cells is key to overcoming radio-resistance in lung cancer. Herein, we demonstrated that radiation exacerbates fibrosis and acted as a critical driver for fibroblast proliferation and migration by promoting tumor cell secretion of high mobility group box 1(HMGB1), a key regulator of tumor progression and metastasis. Mechanistic analysis revealed that HMGB1 activated the PI3K-AKT pathway via TLR4, driving the transformation of CAFs into myCAFs subtypes. To block HMGB1 and enhance radiotherapy, we encapsulated the HMGB1 inhibitor DPG into tumor-targeted liposomes (DPG-Lipo) for combined tumor radiotherapy. The results showed that HMGB1 inhibition not only prevented CAFs activation and boosted radiotherapy effectiveness but also promoted immune infiltration, including CD8 T cells and DCs. Additionally, the reduction of MMP2 and VEGF in tumor tissues further suggested that combined targeted therapy could also inhibit tumor metastasis and invasion. Our findings reveal the relationship between lung cancer radio-resistance and CAFs, highlighting the significance of targeting HMGB1 to inhibit CAFs in enhancing radiotherapy sensitivity.