Development of multifunctional stimuli-responsive nanomedicine is appealing for effective cancer treatment. Herein, we utilize the biocompatible CaCO 3 nanoparticles as the template to guide the formation of pH-dissociable hollow coordination nanostructures, in which meso-tetra-(4-carboxyphenyl)porphine (TCPP), a sonosensitizer, acts as the organic bridging molecule and ferric ion serves as the metallic center. L-buthionine sulfoximine (BSO), an inhibitor for glutathione (GSH) biosynthesis, can be simultaneously loaded during the preparation of TCPP-Fe@CaCO 3 , obtaining BSO-TCPP-Fe@CaCO 3 with pH-responsive dissociation to endow fast release of Ca 2+ and BSO under an acidic tumor microenvironment. Such BSO-TCPP-Fe@CaCO 3 confers synergistic oxidative stress amplification via intracellular Ca 2+ -overloading-induced mitochondria damage, BSO-mediated GSH depletion, and TCPP-mediated sonodynamic therapy (SDT), leading to remarkable cell death. Consequently, tumors on the mice treated with BSO-TCPP-Fe@-CaCO 3 administration and subsequent ultrasound exposure are effectively suppressed. Our work thus highlights a facile strategy to prepare pH-dissociable nanomedicine for effective SDT treatment of tumors via triple amplification of tumor oxidative stress.

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Radiotherapy is widely exploited for the treatment of a large range of cancers in clinic, but its therapeutic effectiveness is seriously crippled by the tumor immunosuppression, mainly driven by the altered metabolism of cancer cells. Here, a pH‐responsive nanomedicine is prepared by coating calcium carbonate (CaCO3) nanoparticles with 4‐phenylimidazole (4PI), an inhibitor against indoleamine 2,3‐dioxygenase 1 (IDO‐1), together with zinc ions via the coordination reaction, aiming at reinforcing the treatment outcome of radiotherapy. The obtained pH‐responsive nanomedicine, coined as acidity‐IDO1‐modulation nanoparticles (AIM NPs), is able to instantly neutralize protons, and release 4PI to suppress the IDO1‐mediated production of kynurenine (Kyn) upon tumor accumulation. As a result, treatment with AIM NPs can remarkably enhance the therapeutic efficacy of radiotherapy against both murine CT26 and 4T1 tumors by eliciting potent antitumor immunity. Furthermore, it is shown that such combination treatment can effectively suppress the growth of untreated distant tumors via the abscopal effect, and result in immune memory responses to reject rechallenged tumors. This work highlights a novel strategy of simultaneous tumor acidity neutralization and IDO1 inhibition to potentiate radiotherapy, with great promises to suppress tumor metastasis and recurrence by eliciting robust antitumor immunity.

Microwave ablation (MWA) as a local tumor ablation strategy suffers from posttreatment tumor recurrence. Development of adjuvant biomaterials to potentiate MWA is therefore of practical significance. Here, the high concentration of Ca 2+ fixed by alginate as Ca 2+ -surplus alginate hydrogel shows enhanced heating efficiency and restricted heating zone under microwave exposure. The high concentration of extracellular Ca 2+ synergizes with mild hyperthermia to induce immunogenic cell death by disrupting intracellular Ca 2+ homeostasis. Resultantly, Ca 2+ -surplus alginate hydrogel plus MWA can ablate different tumors on both mice and rabbits at reduced operation powers. This treatment can also elicit antitumor immunity, especially if synergized with Mn 2+ , an activator of the stimulation of interferon genes pathway, to suppress the growth of both untreated distant tumors and rechallenged tumors. This work highlights that in situ–formed metallo-alginate hydrogel could act as microwave-susceptible and immunostimulatory biomaterial to reinforce the MWA therapy, promising for clinical translation.

Radiotherapy (RT), as one of the main methods in the clinical treatment of various malignant tumors, would induce systemic immunotherapeutic effects by triggering immunogenic cell death (ICD) of cancer cells. However, the antitumor immune responses produced by RT-induced ICD alone usually are not robust enough to eliminate distant tumors and thus ineffective against cancer metastases. Herein, a biomimetic mineralization method for facile synthesis of MnO 2 nanoparticles with high antiprogrammed death ligand 1 (αPDL1) encapsulation efficiency (αPDL1@MnO 2 ) is proposed to reinforce RT-induced systemic antitumor immune responses. This therapeutic nanoplatformsmediated RT can significantly improve the killing of tumor cells and effectively evoke ICD by overcoming hypoxia-induced radioresistance and reprogramming the immunosuppressive tumor microenvironment (TME). Furthermore, the released Mn 2+ ions from αPDL1@MnO 2 under acidic tumor pH can activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and facilitate the dendritic cells (DCs) maturation. Meanwhile, αPDL1 released from αPDL1@MnO 2 nanoparticles would further promote the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) and trigger systemic antitumor responses, resulting in a strong abscopal effect to effectively inhibit tumor metastases. Overall, the biomineralized MnO 2 -based nanoplatforms offer a simple strategy for TME modulation and immune activation, which are promising for enhanced RT immunotherapy.