Engineering of Cascade-Responsive Nanoplatform to Inhibit Lactate Efflux for Enhanced Tumor Chemo-Immunotherapy

As an increased product of high-rate aerobic glycolysis in tumors, lactate could regulate the immunosuppressive tumor microenvironment (TME). A PEG-CDM surface modified, GSH-dependent responsive hollow mesoporous organosilica nanoplatform loaded with hydroxycamptothecin (HCPT) and siMCT-4 was administrated for synergistic tumor chemo-immunotherapy. The nanoplatform cascaded responded to the weak acid TME and the high level of GSH in tumor cells. HCPT and siMCT-4 were continuously released from the nanoplatform for chemotherapy and inhibiting intracellular lactate efflux. The increased intracellular lactate and HCPT effectively induced tumor cell apoptosis. Moreover, the decreased extracellular lactate polarized tumor-associated macrophages (TAMs) phenotype from M2 type to M1 type and restored CD8⁺ T cell activity in vivo. The results demonstrated that the nanoplatform effectively removed the immunosuppressive TME, inhibited tumor growth, and suppressed lung metastasis of B16F10 cells and 4T1 cells via the combination of inhibiting lactate efflux and chemotherapy. Accordingly, it suggested a strategy to transform immunosuppressive tumors into "hot" tumors and inhibit the tumor growth with high efficiency in vivo.