Sulfate Radical Based In Situ Vaccine Boosts Systemic Antitumor Immunity via Concurrent Activation of Necroptosis and STING Pathway

Abstract In situ vaccine (ISV) can provoke systemic anti‐tumor immunity through the induction of immunogenic cell death (ICD). The development of ISV technology has been restricted by the limited and suboptimal ICD driven tumor antigen production which are currently relying on chemo‐drugs, photo‐/radio‐sensitizers, oncolytic‐virus and immunostimulatory agents. Herein, a sulfate radical (SO₄^·−) based ISV is reported that accomplishes superior tumor immunotherapy dispense from conventional approaches. The ISV denoted as P‐Mn‐LDH is constructed by intercalating peroxydisulfate (PDS, a precursor of SO₄^·−) into manganese layered double hydroxide nanoparticles (Mn‐LDH). This design allows the stabilization of PDS under ambient condition, but triggers a Mn²⁺ mediated PDS decomposition in acidic tumor microenvironment (TME) to generate in situ SO₄^·−. Importantly, it is found that the SO₄^·‐ radicals not only effectively kill cancer cells, but also induce a necroptotic cell death pathway, leading to robust ICD signaling for eliciting adaptive immunity. Further, the P‐Mn‐LDH can activate the stimulator of interferon genes (STING) pathway to further boost anti‐tumor immunity. Collectively, the P‐Mn‐LDH based ISV exhibited potent activity in inhibiting tumor growth and lung metastasis. When combined with immune checkpoint inhibitor, significant inhibition of distant tumors is achieved. This study underpins the promise of SO₄^·‐ based vaccine technology for cancer immunotherapy.