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The chemo-immunotherapy has become a highly prospective method for cancer treatment, and it has been known that chemotherapeutic drugs [ e.g. , doxorubicin (DOX)] could trigger antitumor immune responses. Yet, insufficient tumor penetrability and weak immunogenic cell death (ICD) severely limits the therapeutic effect of chemo-immunotherapy against cancer. Herein, we report the design of DOX-loaded silica nanocarriers (DOX@HMSPHs) with hyaluronidase functionalization, which could increase the permeability of drug and induce enhanced ICD effect through the degradation of hyaluronic acid (HA) in the extracellular matrix (ECM). Interestingly, the controlled release of DOX from DOX@HMSPHs in the acidic microenvironment induced ICD of tumor cells to release tumor antigens and damage-associated molecular patterns, promoting the antigen-presentation of dendritic cells (DCs) and the activation of specific tumor immunity. Moreover, HMSPHs could be used as an immune adjuvant to promote maturation of DCs, thereby promoting the activation of tumor infiltrating cytotoxic T lymphocytes. This strategy presents a concept to improve the efficacy of chemo-immunotherapy through degradation of HA in the ECM.