Platinum (Pt)-based anticancer agents exhibit a lack of selectivity in the treatment of osteosarcoma, resulting in significant toxicity. Furthermore, immune surveillance withinthe tumor microenvironment impedes the uptake of platinum drugs by osteosarcoma cells. To overcome these challenges, an oxaliplatin-based Pt prodrug amphiphile (Lipo-OXA-ALN) was designed and synthesized by incorporatingan osteosarcoma-targeting alendronate (ALN) alongside a lipid tail. The lipid nanoparticles (ALN-OXA), which self-assemble from Lipo-OXA-ALN, enhanced intracellular platinum uptake due to their superior Ca trapping ability and significantly inhibit osteosarcoma cell activity. Moreover, ALN-OXA exhibited potent targeting capabilities, effectively suppressing osteosarcoma growth while preventing bone destruction. Importantly, ALN-OXA induces a series of immune responses characterized by the activation of immune cells, maturation of dendritic cells, and secretion of related cytokines, followed by the activation and infiltration of T lymphocytes and a significant increase in the ratio of cytotoxic T cells. Additionally, the ratio of M1/M2 macrophages increased markedly after ALN-OXA treatment, suggesting potential reprogramming of the tumor microenvironment by ALN-OXA. Overall, the improved therapeutic efficacy against osteosarcoma demonstrates that the Pt prodrug amphiphile represents a promising strategy for combining targeted chemotherapy with strategies aimed at reversing immune suppression. STATEMENT OF SIGNIFICANCE: Platinum (Pt)-based chemotherapy for osteosarcoma faces challenges due to poor tumor selectivity, leading to suboptimal efficacy and increased toxicity. Additionally, the osteosarcoma microenvironment impedes effective drug delivery. To overcome these limitations, we developed an oxaliplatin-based Pt prodrug nanoparticle (ALN-OXA) for targeted chemo-immunotherapy. ALN-OXA showed significant in vivo efficacy, effectively preventing bone damage and enhancing the immune microenvironment to improve treatment outcomes. This innovative approach not only targets the tumor more efficiently but also boosts immune response, offering a promising strategy for tumor blockade, tumor starvation, and other therapeutic applications in osteosarcoma treatment.