Background <p>Concurrent systemic chemotherapy and local radiotherapy represent the clinical standard of care for a broad spectrum of malignant tumors, and these modalities can elicit endogenous anti-tumor immune responses. However, the hypoxic tumor microenvironment (TME) of solid tumors severely impairs the therapeutic efficacy of chemotherapy, radiotherapy, and immunotherapy, leading to treatment failure and tumor progression.</p> Results <p>We engineered a platinum–osmium hybrid nanozyme (PO) via the self-assembly of an oxaliplatin (Oxa) prodrug, osmium, and polyvinylpyrrolidone, which potentiates the synergy of combined therapy through cascade catalytic reactions. PO exhibits catalase-like activity to decompose endogenous hydrogen peroxide into oxygen, thereby reversing tumor hypoxia, and glutathione peroxidase-like activity to deplete intracellular glutathione, which synergistically augments the efficacy of chemotherapy and radiotherapy. Under the reductive TME, PO is activated to release bioactive Oxa, in conjunction with osmium-mediated radiosensitization, PO induces severe DNA damage, activates the cyclic GMP-AMP synthase-stimulator of interferon genes pathway, and triggers robust immunogenic cell death, thus eliciting a systemic anti-tumor immune response. Furthermore, PO modulates the expression of metastasis-associated epithelial-mesenchymal transition proteins to inhibit tumor invasion and metastasis. Both in vitro and in vivo studies demonstrate that PO exerts superior therapeutic efficacy against metastatic colorectal cancer compared with free Oxa. Notably, the biodegradable nature of PO minimizes systemic toxicity and ensures favorable biocompatibility.</p> Conclusions <p>This work presents a degradable hybrid nanozyme strategy that integrates chemotherapeutic, radiosensitizing, and immunomodulatory functions to overcome the hypoxic TME barrier, thus improving the therapeutic outcome of hypoxic and metastatic colorectal cancer.</p> Graphical Abstract <p></p>