A nanoscale innate immune multiplier amplifies immunogenic cell death triggered by oxaliplatin via enhancing systemic and trained immunity

Inducing immunogenic cell death (ICD) of cancer cells is the key for cytotoxic drugs to improve the synergy with immunotherapy. However, due to the immunosuppressive microenvironment and the cytotoxicity differences of drugs, ICD effects are often insufficient and difficult to effectively and durably activate anti-tumor immune responses. Here, we performed a network meta-analysis (NMA) based on clinical data of gastrointestinal cancer and identified oxaliplatin (Oxp) as an effective ICD-inducing drug. Meanwhile, to overcome the negative effects of immunosuppressive microenvironment on ICD, we constructed a nanoscale innate immune multiplier (NIIM) composed of nano-granulated manganous zoledronate, and designed a systemic delivery strategy to achieve the superposition of innate immune responses from multiple sites and amplify the ICD effect of Oxp. NIIM was first targeted to the tumor tissue, where it concurrently engaged tumor cells and innate immunocytes to reverse the immunosuppressive microenvironment. Following intravenous administration, NIIM was also distributed to the spleen, where it activated Ly6C⁺ inflammatory monocytes, directly augmenting the phagocytosis and elimination of tumor cells, and inducing the tumor-killing efficacy by cytotoxic T cells. Additionally, NIIM modulated the composition of hematopoietic progenitor cells in the bone marrow, inducing a durable innate immune response through trained immunity. The superposition of these immune effects allowed NIIM to significantly enhance the efficacy of oxaliplatin in gastrointestinal cancers after only one single injection. In summary, this strategy of simultaneously activating intratumoral, systemic, and trained immunity based on intravenous NIIM provides an effective new approach to amplify ICD of cytotoxic drugs and achieve the efficient synergy of chemotherapy with immunotherapy.