Background Immune checkpoint blockade (ICB) therapies have reshaped tumor treatment by activating the antitumor immune response. However, the antitumor effect of ICB is seriously restricted by the immunosuppressive tumor microenvironment (ITM). A variety of strategies to alleviate the ITM have been investigated. Direct regulation of lactate metabolism in tumor microenvironment holds promise for ITM modulation. Results Glutathione (GSH) -responsive hollow mesoporous organosilicon (HMOP) was successfully fabricated, with monocarboxylate transporter 1/4 inhibitor (diclofenac, DC) and lactate oxidase (LOD) were loaded in/onto the HMOP (designed as DC-HMOP-LOD). DC-HMOP-LOD could spontaneously be biodegraded in tumor microenvironment due to disulfide bonds, and then DC/LOD could be released to exhaust intra/extracellular lactate. Consequently, lactate depletion induced an immunocompetent tumor microenvironment by activating immune-promoting cells including dendritic cells, CD4+ T cells, CD8+ T cells, and natural killer cells, and inactivating immunosuppressive cells containing tumor-associated macrophages and myeloid-derived suppressor cells, ultimately strengthening the antitumor effect of ICB therapy. Conclusion DC-HMOP-LOD effectively hindered the transmission of lactate and directly oxidized lactate, collaboratively depleting lactate in the TME. The synergetic depletion reversed the ITM and could improve the antitumor effects of aPD1-based immunotherapy.

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