DNA damage-encouraged Mn-As-based nanoreactors reshape intratumoral cell phenotypes to recover immune surveillance and potentiate anti-tumor immunity

Arsenic trioxide is a promising anti-tumor approach based on cytotoxic reactive oxygen species (ROS). However, the harsh post-encapsulation conditions, complex tumor microenvironment including spontaneous ataxia telangiectasia mutated kinase (ATM)-mediated DNA damage repair, programmed death ligand 1 (PD-L1) upregulation-evoked immune escape often compromised this anti-tumor effect. To address these concerns, we leverage DNA damage-encouraged liposomes that load ATM inhibitor (ATMi) to in-situ yield Mn-As nanocompounds for reshaping intratumoral cell phenotypes, recovering immune surveillance and potentiating antitumor immunity against tumor progression and metastasis. The in-situ synthesized Mn-As nanocompounds can respond to acidic tumor microenvironment to release Mn2+ and As3+ for producing ROS, repolarizing tumor-associated macrophages (TAMs) and mitigating immunosuppressive tumor microenvironment. The loaded ATMi can inhibit DNA damage repair and reshape tumor cell phenotypes via down-regulating ROS-encouraged PD-L1 expression, which recovers immune surveillance and magnifies ROS accumulation. Systematic experiments indicate that these actions induced by such DNA damage-encouraged nanoreactors aggravate ROS-induced DNA destruction, reprogramme TAMs and tumor cells, and potentiate systematic anti-tumor immunity to successfully suppress the progression and metastasis of orthotopic breast tumor, thus serving as a more effective anticancer strategy.