Zhaochen Tong, Yi Peng, D Wang, Lingpu Zhang, Sijie Wen, Zixin Li, Qing Deng, J Z Zeng, Fang Wang, Yueqiang Zhang, Chuqi Cong, Weiguo Wang, Jinglei Miao, Jinsong Li, Zheng Cao, Haihua Xiao, Shijie Chen
ABSTRACT Chemoresistance and immune suppression are pervasive in osteosarcoma (OS), severely limiting the efficacy of cisplatin. Aberrant glycolysis and excessive lactate accumulation not only promote tumor resistance but are also associated with impaired antitumor immunity, in part through cGAS lactylation, a lactate‐associated post‐translational modification of cGAS linked to attenuated cGAS–STING signaling. Here, we have developed a bone‐targeted nanotherapeutic, MALss Gi/A @Mi, co‐loaded with the GLUT1 inhibitor WZB117 and the MCT1 inhibitor BAY8002, to restore immunometabolic balance in OS. MALss Gi/A @Mi enables glutathione‐responsive release in the reductive tumor microenvironment and simultaneously inhibits the overexpression of GLUT1 and MCT1, leading to coordinated suppression of lactate production and transport. This material‐mediated metabolic reprogramming alleviates cGAS lactylation, promotes restoration of cGAS–STING signaling, and enhances antitumor immune responses. Both in vitro and in vivo studies demonstrate that MALss Gi/A @Mi markedly sensitizes OS to cisplatin, remodels the immunosuppressive tumor microenvironment, and suppresses tumor growth. Importantly, robust therapeutic efficacy is further validated in a patient‐derived xenograft model established from post‐chemotherapy recurrent OS, highlighting its translational potential. Collectively, this work presents a nanomaterial‐enabled strategy to overcome chemoresistance through modulation of the metabolic–immune axis.