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Immune checkpoint blockade (ICB) has significantly advanced cancer immunotherapy, yet its patient response rates are generally low. Vaccines, including immunostimulant‐adjuvanted peptide antigens, can improve ICB. The emerging neoantigens generated by cancer somatic mutations elicit cancer‐specific immunity for personalized immunotherapy; the novel cyclic dinucleotide (CDN) adjuvants activate stimulator of interferon genes (STING) for antitumor type I interferon (IFN‐I) responses. However, CDN/neoantigen vaccine development has been limited by the poor antigen/adjuvant codelivery. Here, pH‐responsive CDN/neoantigen codelivering nanovaccines (NVs) for ICB combination tumor immunotherapy are reported. pH‐responsive polymers are synthesized to be self‐assembled into multivesicular nanoparticles (NPs) at physiological pH and disassembled at acidic conditions. NPs with high CDN/antigen coloading are selected as NVs for CDN/antigen codelivery to antigen presenting cells (APCs) in immunomodulatory lymph nodes (LNs). In the acidic endosome of APCs, pH‐responsive NVs facilitate the vaccine release and escape into cytosol, where CDNs activate STING for IFN‐I responses and antigens are presented by major histocompatibility complex (MHC) for T‐cell priming. In mice, NVs elicit potent antigen‐specific CD8 + T‐cell responses with immune memory, and reduce multifaceted tumor immunosuppression. In syngeneic murine tumors, NVs show robust ICB combination therapeutic efficacy. Overall, these CDN/neoantigen‐codelivering NVs hold the potential for ICB combination tumor immunotherapy.

Cyclic dinucleotides (CDNs), such as c‐di‐GMP (CDG), are agonists for stimulator of interferon genes (STING) and are promising for cancer immunotherapy. Yet, the therapeutic efficacy of CDNs has been limited by poor delivery and biostability. Here, STING‐activating DNA nanovaccines (STING‐NVs) are developed, which biostabilize, deliver, and conditionally release CDG in the endosome of immune cells, elicit potent antitumor immune responses in murine and human immune cells, ameliorate immunosuppression in vitro and in the tumor microenvironment, and mediate potent cancer immunotherapy in a murine melanoma model. STING‐NVs have PLA‐b‐PEG in the core and cytosine (C)‐rich i‐motif DNA on the surface. i‐Motif DNA undergoes characteristic pH‐responsive conformational switch, allowing efficient CDG loading via C:G base pairing at physiological pH, and CDG release in sensitive response to acidic environment such as cell endosome. STING‐NVs protect CDG from enzymatic degradation. STING‐NVs facilitate cell delivery. Remarkably, STING‐NVs promote the endosome escape of CDG by ninefold, and potentiate antitumor immunity. STING‐NVs repolarize immunosuppressive M2‐like macrophages into antitumor M1‐like macrophages in vitro and in the tumor microenvironment of melanoma. In a poorly immunogenic murine melanoma model, intralesional STING‐NVs outperform liposomal CDG and fluoride‐CDG for melanoma immunotherapy. These results suggest the great potential of STING‐NVs for cancer immunotherapy.