Lactate/Cysteine\nDual-Consuming Probiotic–Nanomedicine\nBiohybrid System for Enhanced Cancer Chemo-Immunotherapy

Immunotherapy is revolutionizing oncology, but its therapeutic\nefficiency is still limited by the off-target toxicities and poor\nantitumor immune responses. By integrating the drug-loaded nanoparticles\n(DMnSH) with the unique metabolic traits of <i>Veillonella parvula</i> (Vei), a probiotic–nanomedicine conjugate Vei@DMnSH biohybrid\nis elaborately designed for enhanced cancer chemo-immunotherapy. Specifically,\nVei@DMnSH can accumulate in hypoxic tumor sites and simultaneously\nconsume lactate and cysteine to reverse the lactate-associated immunosuppression\nand impede the biosynthesis of GSH. In addition, the DMnSH nanoparticles\nwill rapidly deplete intracellular GSH and disassemble to release\nDOX and Mn<sup>2+</sup>. Accompanied by the two-pronged GSH depletion,\nthe Mn<sup>2+</sup>-mediated Fenton-like reaction can effectively\ngenerate oxidative hydroxyl radicals to induce heavy redox imbalance.\nCombined with the therapeutic effect of DOX, robust immunogenic cell\ndeath is provoked and subsequently activates antitumor adaptive immunity\nwith a tumor suppression rate over 82%, synergistically enhancing\nthe therapeutic outcomes of cancer chemo-immunotherapy.