| Summary: | Abstract Tumor heterogeneity makes routine drugs difficult to penetrate solid tumors, limiting their therapy efficacies. Based on high tissue penetrability of hydrogen molecules (H2) and ultrasound (US) and the immunomodulation effects of H2 and lactic acid (LA), this work proposes a novel strategy of US‐driven piezoelectrocatalytic tumor immunoactivation for high‐efficacy therapy of deep tumors by piezoelectrocatalytic hydrogen generation and LA deprivation. A kind of US‐responsive piezoelectric SnS nanosheets (SSN) is developed to realize US‐triggered local hydrogen production and simultaneous LA deprivation in deep tumors. The proof‐of‐concept experiments which are executed on an orthotopic liver cancer model have verified that intratumoral SSN‐medicated piezoelectrocatalytically generated H2 liberates effector CD8+ T cells from the immunosuppression of tumor cells through down‐regulating PD‐L1 over‐expression, and simultaneous LA deprivation activates CD8+ T cells by inhibiting regulatory T cells, efficiently co‐activating tumor immunity and achieving a high outcome of liver tumor therapy with complete tumor eradication and 100% mice survival. The proposed strategy of US‐driven piezoelectrocatalytic tumor immunoactivation opens a safe and efficient pathway for deep tumor therapy.
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