Ferritin (Fn) is considered a promising carrier for targeted delivery to tumors, but the successful application in vivo has not been fully achieved yet. Herein, strong evidence is provided that the Fn receptor is expressed in liver tissues, resulting in an intercept effect in regards to tumor delivery. Building on these observations, a biomineralization technology is rationally designed to shield Fn using a calcium phosphate (CaP) shell, which can improve the delivery performance by reducing Fn interception in the liver while re-exposing it in acidic tumors. Moreover, the selective dissolution of the CaP shell not only neutralizes the acidic microenvironment but also induces the intratumoral immunomodulation and calcification. Upon multiple cell line and patient-derived xenografts, it is demonstrated that the elaboration of the highly flexible Fn@CaP chassis by loading a chemotherapeutic drug into the Fn cavity confers potent antitumor effects, and additionally encapsulating a photosensitizer into the outer shell enables a combined chemo-photothermal therapy for complete suppression of advanced tumors. Altogether, these results support Fn@CaP as a new nanoplatform for efficient modulation of the tumor microenvironment and targeted delivery of diverse therapeutic agents.