A new study reveals that collagen acts as a physical barrier in solid tumors, hindering immune cell infiltration, oxygen perfusion, and immune suppression. Radiotherapy (RT) can induce DNA damage but is limited by tumor hypoxia and collagen. Additionally, RT can induce immunogenic cell death (ICD), which recruits T cells to tumors, but this is also limited by collagen. Current methods to deplete collagen, such as collagenase or pirfenidone, are ineffective due to lack of tumor targeting and side effects. Moreover, these methods may increase PD-L1 expression, which acts as an immune checkpoint inhibitor and DNA damage repair accelerator, limiting RT efficacy. The study demonstrates that inhibiting mitochondrial oxidative phosphorylation (OXPHOS) using oxidative phosphorylation inhibitors like Lonidamine (LND) can effectively regulate multiple immune pathways by simultaneously suppressing collagen, PD-L1, and TGF-β. By combining LND with a mitochondria-targeted molecule IR-68 and encapsulating it in liposomes to form IR-LND@Lip nanoadjuvants, the study shows that this approach enhances RT by increasing DNA damage, converting cold tumors into hot ones through immune activation, and effectively sensitizing tumors to RT. The combination of RT and IR-LND@Lip significantly suppresses the growth of bladder and breast tumors. The IR-LND@Lip nanoadjuvants were synthesized and characterized, showing good stability, size, and zeta potential. The nanoadjuvants effectively inhibited collagen, PD-L1, and TGF-β, reversed tumor hypoxia, and enhanced T cell infiltration and activation. In vivo studies showed that IR-LND@Lip significantly improved the efficacy of RT by reducing PD-L1 expression, inhibiting TGF-β, and decreasing tumor growth and metastasis. The nanoadjuvants were well tolerated, with no significant toxicity to major organs. The study highlights the potential of IR-LND@Lip as a promising adjuvant for RT in solid tumors.A new study reveals that collagen acts as a physical barrier in solid tumors, hindering immune cell infiltration, oxygen perfusion, and immune suppression. Radiotherapy (RT) can induce DNA damage but is limited by tumor hypoxia and collagen. Additionally, RT can induce immunogenic cell death (ICD), which recruits T cells to tumors, but this is also limited by collagen. Current methods to deplete collagen, such as collagenase or pirfenidone, are ineffective due to lack of tumor targeting and side effects. Moreover, these methods may increase PD-L1 expression, which acts as an immune checkpoint inhibitor and DNA damage repair accelerator, limiting RT efficacy. The study demonstrates that inhibiting mitochondrial oxidative phosphorylation (OXPHOS) using oxidative phosphorylation inhibitors like Lonidamine (LND) can effectively regulate multiple immune pathways by simultaneously suppressing collagen, PD-L1, and TGF-β. By combining LND with a mitochondria-targeted molecule IR-68 and encapsulating it in liposomes to form IR-LND@Lip nanoadjuvants, the study shows that this approach enhances RT by increasing DNA damage, converting cold tumors into hot ones through immune activation, and effectively sensitizing tumors to RT. The combination of RT and IR-LND@Lip significantly suppresses the growth of bladder and breast tumors. The IR-LND@Lip nanoadjuvants were synthesized and characterized, showing good stability, size, and zeta potential. The nanoadjuvants effectively inhibited collagen, PD-L1, and TGF-β, reversed tumor hypoxia, and enhanced T cell infiltration and activation. In vivo studies showed that IR-LND@Lip significantly improved the efficacy of RT by reducing PD-L1 expression, inhibiting TGF-β, and decreasing tumor growth and metastasis. The nanoadjuvants were well tolerated, with no significant toxicity to major organs. The study highlights the potential of IR-LND@Lip as a promising adjuvant for RT in solid tumors.