Radiation therapy can potentially induce immunogenic cell death, thereby priming anti-tumor adaptive immune responses. However, radiation-induced systemic immune responses are very rare and insufficient to meet clinical needs. Here, we demonstrate a synergetic strategy for boosting radiation-induced immunogenic cell death by constructing gadolinium-hemin based nanoscale coordination polymers to simultaneously perform X-ray deposition and glutathione depletion. Subsequently, immunogenic cell death is induced by sensitized radiation to potentiate checkpoint blockade immunotherapies against primary and metastatic tumors. In conclusion, nanoscale coordination polymers-sensitized radiation therapy exhibits biocompatibility and therapeutic efficacy in preclinical cancer models, and has the potential for further application in cancer radio-immunotherapy.

The irradiated tumor itself represents an opportunity to establish endogenous in situ vaccines. However, such in situ cancer vaccination (ISCV) triggered by radiation therapy (RT) alone is very weak and hardly elicits systemic anticancer immunity. In this study, we develop two-dimensional risedronate-manganese nanobelts (RMn-NBs) as an adjuvant for RT to address this issue. RMn-NBs exhibit good T₂ magnetic resonance imaging performance and enhanced Fenton-like catalytic activity, which induces immunogenic cell death. RMn-NBs can inhibit the HIF-1α/VEGF axis to empower RT and synchronously activate the cGAS/STING pathway for promoting the secretion of type I interferon, thereby boosting RT-triggered ISCV and immune checkpoint blockade therapy against primary and metastatic tumors. RMn-NBs as a nano-adjuvant for RT show good biocompatibility and therapeutic efficacy, presenting a promising prospect for cancer radiotherapy and immunotherapy.

Radiation-induced in situ tumor vaccination alone is very weak and insufficient to elicit robust antitumor immune responses. In this work, we address this issue by developing chiral vidarabine monophosphate-gadolinium nanowires (aAGd-NWs) through coordination-driven self-assembly. We elucidate the mechanism of aAGd-NW assembly and characterize their distinct features, which include a negative surface charge, ultrafine topography, and right-handed chirality. Additionally, aAGd-NWs not only enhance X-ray deposition but also inhibit DNA repair, thereby enhancing radiation-induced in situ vaccination. Consequently, the in situ vaccination induced by aAGd-NWs sensitizes radiation enhances CD8⁺ T-cell-dependent antitumor immunity and synergistically potentiates the efficacy immune checkpoint blockade therapies against both primary and metastatic tumors. The well-established aAGd-NWs exhibit exceptional therapeutic capacity and biocompatibility, offering a promising avenue for the development of radioimmunotherapy approaches.

Glycolytic activity of cancer cells not only reduces their vulnerability to cuproptosis but also heightens the immunosuppressive state of the tumor microenvironment (TME). Our study introduces a nanoplatform called dual-remodeling cuproptosis-inducing agent with hybrid cell membrane coating (DREAM), which is crafted to simultaneously modify the metabolic and immunological landscapes of the TME to enhance cuproptosis-driven immunotherapy. This platform exploits cancer-cell-derived membranes for homologous targeting, enhancing tumor specificity, intratumoral penetration, and intracellular copper delivery. DREAM’s disruption of glycolysis intensifies the copper overload, triggering cuproptosis in cancer cells. Additionally, it alleviates immunosuppression and bolsters immune responses facilitated by the immunogenic cell death from cuproptosis, further potentiated by the immunostimulatory effect of M1 macrophage membranes. The outcome is a pronounced efficacy in curbing tumor growth and distant metastasis in squamous cell carcinoma and also in suppressing melanoma proliferation and lung metastasis. This research underscores the vital interaction among inhibiting glycolysis, enhancing sensitivity to cuproptosis, and activating immune responses, thereby paving a feasible and integrated pathway in cancer immunotherapy.