Immunotherapy is revolutionizing oncology, but its therapeutic efficiency is still limited by the off-target toxicities and poor antitumor immune responses. By integrating the drug-loaded nanoparticles (DMnSH) with the unique metabolic traits of Veillonella parvula (Vei), a probiotic–nanomedicine conjugate Vei@DMnSH biohybrid is elaborately designed for enhanced cancer chemo-immunotherapy. Specifically, Vei@DMnSH can accumulate in hypoxic tumor sites and simultaneously consume lactate and cysteine to reverse the lactate-associated immunosuppression and impede the biosynthesis of GSH. In addition, the DMnSH nanoparticles will rapidly deplete intracellular GSH and disassemble to release DOX and Mn2+. Accompanied by the two-pronged GSH depletion, the Mn2+-mediated Fenton-like reaction can effectively generate oxidative hydroxyl radicals to induce heavy redox imbalance. Combined with the therapeutic effect of DOX, robust immunogenic cell death is provoked and subsequently activates antitumor adaptive immunity with a tumor suppression rate over 82%, synergistically enhancing the therapeutic outcomes of cancer chemo-immunotherapy.

Lactate/Cysteine Dual-Consuming Probiotic–Nanomedicine Biohybrid System for Enhanced Cancer Chemo-Immunotherapy