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Chemoimmunotherapy‐induced antitumor immune response is highly dependent on tumor autophagy. When tumor cells are treated with chemoimmunotherapy, timely overactivated autophagy can not only lead more tumor cells to death, but also participate in the endogenous antigen presentation and immune stimulators secretion of dying cells, thus plays a vital role. However, timely and accurately overactivated tumor autophagy during chemoimmunotherapy is of great difficulty. Here, an on‐demand autophagy cascade amplification nanoparticle (ASN) is reported to boost oxaliplatin‐induced cancer immunotherapy. ASN is prepared by self‐assemble of autophagy‐responsible C‐TFG micelle and is followed by electrostatic binding of oxaliplatin prodrug (HA‐OXA). After entering tumor cells, the HA‐OXA shell of ASN first responds to the reduction microenvironment and releases oxaliplatin to trigger tumor immunogenic cell death and mildly stimulates tumor autophagy. Then, the exposed C‐TFG micelle can sensitively respond to oxaliplatin‐induced autophagy and release a powerful autophagy inducer STF‐62247, which precisely transforms autophagy to “overactivated” condition, leading tumor cells to autophagic death and enhance subsequent tumor antigen processing of the dying cells. In CT26 tumor‐bearing mice, ASN exhibits optimal immune stimulation and antitumor efficiency due to its on‐demand autophagy induction ability.

Metastasis remains the main driver of mortality in patients suffering from cancer because of the refractoriness resulting from the multi‐phase metastatic cascade. Herein, a multifunctional self‐delivering PBA‐LMWH‐TOS nanoparticle (PLT NP) is established that acts as both nanocarrier and anti‐metastatic agent with effects on most hematogenous metastases of cancers. The hydrophilic segment (low molecular weight heparin, LMWH) inhibits the interactions between tumor cells and platelets. The hydrophobic segment (d‐α‐tocopheryl succinate, TOS) could inhibit the expression of matrix metalloproteinase‐9 (MMP‐9) in B16F10 cells which is first reported in this article. Surprisingly, even the blank NPs showed excellent anti‐metastatic capacity in three mouse models by acting on different phases of the metastatic cascade. Moreover, the overexpression of sialic acid (SA) residues on tumor cells is implicated in the malignant and metastatic phenotypes of cancers. Thus, these 3‐aminophenylboronic acid (PBA)‐modified doxorubicin (DOX)‐loaded NPs offer an efficient approach for the treatment of both solid melanomas and metastases. Furthermore, a simple pH‐sensitive “Fructose (Fru)‐blocking” coping strategy is established to reduce the NP distribution in normal tissues and distinctly increases the accumulation in melanoma tumors. These micellar NPs consisting of biocompatible materials offer a promising approach for the clinical therapy of highly invasive solid tumors and metastases.

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