The stimulator of interferon genes (STING) is an endoplasmic reticulum transmembrane protein that is a target of therapeutics for infectious diseases and cancer. However, early-phase clinical trials of small-molecule STING agonists have shown limited antitumour efficacy and dose-limiting toxicity. Here, we show that a polyvalent STING agonist—a pH-sensitive polymer bearing a seven-membered ring with a tertiary amine (PC7A)—activates innate-immunity pathways through the polymer-induced formation of STING–PC7A condensates. In contrast to the natural STING ligand 2′,3′-cyclic-GMP-AMP (cGAMP), PC7A stimulates the prolonged production of pro-inflammatory cytokines by binding to a non-competitive STING surface site that is distinct from the cGAMP binding pocket. PC7A induces antitumour responses that are dependent on STING expression and CD8+ T-cell activity, and the combination of PC7A and cGAMP led to synergistic therapeutic outcomes (including the activation of cGAMP-resistant STING variants) in mice bearing subcutaneous tumours and in resected human tumours and lymph nodes. The activation of the STING pathway through polymer-induced STING condensation may offer new therapeutic opportunities.

Though zeolitic imidazole framework (ZIF) emerges as an advanced functional material for small-molecule delivery due to its unique features such as high loading and pH-sensitive degradation, there are extreme short of knowledge regarding its biological functions. To qualify this category of delivery vehicle, ZIF-8 nanoparticles (ZIF-NPs) with or without cargo are engineered and comprehensively investigated in vitro and in vivo. Interestingly, ZIF-NPs demonstrate strong bioadhesion but with limited internalization themselves, which enhance the membrane-mediated ROS and are different from that of inorganic ZnO inducing mitochondria-mediated reactive oxygen species (ROS) without biomembrane damage. Unexpected high concentration is found in lung, probably due to the particle size and distribution of the nanocarriers; however, the drug levels drop dramatically with time, revealing the fast degradation and elimination. At the given doses, ZIF-NPs exhibit reasonably biosafety in animal tests as evidenced by their acceptable system and blood biocompatibilities, and minimal impacts on the liver and renal functions, immune cells, infl ammatory factors, etc. ZIF-NPs with fl uorouracil loading (5F@ZIF-NPs) signifi cantly improve the therapeutic outcome of lung metastasis tumor in a nude mice model. Generally, ZIF-NPs demonstrate unique biological functions in terms of bio-nano interaction, pulmonary accumulation, biocompatibility, and antitumor therapy, which endow them potential as the delivery vehicles.

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Lactate is a key metabolite produced from glycolytic metabolism of glucose molecules, yet it also serves as a primary carbon fuel source for many cell types. In the tumor-immune microenvironment, effect of lactate on cancer and immune cells can be highly complex and hard to decipher, which is further confounded by acidic protons, a co-product of glycolysis. Here we show that lactate is able to increase stemness of CD8+ T cells and augments anti-tumor immunity. Subcutaneous administration of sodium lactate but not glucose to mice bearing transplanted MC38 tumors results in CD8+ T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis reveals increased proportion of stem-like TCF-1-expressing CD8+ T cells among intra-tumoral CD3+ cells, a phenotype validated by in vitro lactate treatment of T cells. Mechanistically, lactate inhibits histone deacetylase activity, which results in increased acetylation at H3K27 of the Tcf7 super enhancer locus, leading to increased Tcf7 gene expression. CD8+ T cells in vitro pre-treated with lactate efficiently inhibit tumor growth upon adoptive transfer to tumor-bearing mice. Our results provide evidence for an intrinsic role of lactate in anti-tumor immunity independent of the pH-dependent effect of lactic acid, and might advance cancer immune therapy.