The immunologically “cold” microenvironment of triple negative breast cancer results in resistance to current immunotherapy. Here, we reveal the immunoadjuvant property of gas therapy with cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation to augment aggregation-induced emission (AIE)-active luminogen (AIEgen)-based photoimmunotherapy. A virus-mimicking hollow mesoporous tetrasulfide-doped organosilica is developed for co-encapsulation of AIEgen and manganese carbonyl to fabricate gas nanoadjuvant. As tetra-sulfide bonds are responsive to intratumoral glutathione, the gas nanoadjuvant achieves tumor-specific drug release, promotes photodynamic therapy, and produces hydrogen sulfide (H₂S). Upon near-infrared laser irradiation, the AIEgen-mediated phototherapy triggers the burst of carbon monoxide (CO)/Mn²⁺. Both H₂S and CO can destroy mitochondrial integrity to induce leakage of mitochondrial DNA into the cytoplasm, serving as gas immunoadjuvants to activate cGAS-STING pathway. Meanwhile, Mn²⁺ can sensitize cGAS to augment STING-mediated type I interferon production. Consequently, the gas nanoadjuvant potentiates photoimmunotherapy of poorly immunogenic breast tumors in female mice.

The immunosuppressive tumor microenvironment in triple-negative breast cancer could hinder the response to thorough immunotherapy and diminish the antitumor efficacy. Although the STING pathway emerges as a promising target to remedy defects, uncertain drug delivery might lead to off-target inflammatory reactions. Here, we manifest a novel phototheranostic agent with an aggregation-induced emission property that guided the pharmacological activation of a STING agonist for photothermal immunotherapy to create an immunologically "hot" tumor. A pyridinium rotor strategy is proposed to develop a positively charged TBTP-Bz, which is stably coincorporated with a STING agonist MSA-2 into thermal-responsive exosome-liposome hybrid nanoparticles for tumor-targeting delivery. TBTP-Bz exhibits aggregation-enhanced NIR-II emission and a photoacoustic signal, accomplishing real-time tumor tracking. Its photothermal stimulation induces immunogenic cancer cell death and promotes the precise release of MSA-2, thus boosting STING activation and STING-mediated type I interferon production. Significantly, single-dose photoimmunotherapy effectively suppresses abscopal tumor growth and provokes an immune memory effect to inhibit postsurgical recurrent and rechallenged tumors. This demonstrates promising clinical potential for poorly immunogenic breast cancer.

Engineered EVs containing an intelligent core have been designed to interact with a living host environment and function in an ideal situation. This review provides a new insight into design of next-generation EV-based theranostic platforms.

Cytokine therapy, involving interleukin-15 (IL-15), is a promising strategy for cancer immunotherapy. However, clinical application has been limited due to severe toxicity and the relatively low immune response rate, caused by wide distribution of cytokine receptors, systemic immune activation and short half-life of IL-15. Here we show that a biomimetic nanovaccine, developed to co-deliver IL-15 and an antigen/major histocompatibility complex (MHC) selectively targets IL-15 to antigen-specific cytotoxic T lymphocytes (CTL), thereby reducing off-target toxicity. The biomimetic nanovaccine is composed of cytomembrane vesicles, derived from genetically engineered dendritic cells (DC), onto which IL-15/IL-15 receptor α (IL-15Rα), tumor-associated antigenic (TAA) peptide/MHC-I, and relevant costimulatory molecules are simultaneously anchored. We demonstrate that, in contrast to conventional IL-15 therapy, the biomimetic nanovaccine with multivalent IL-15 self-transpresentation (biNV-IL-15) prolonged blood circulation of the cytokine with an 8.2-fold longer half-life than free IL-15 and improved the therapeutic window. This dual targeting strategy allows for spatiotemporal manipulation of therapeutic T cells, elicits broad spectrum antigen-specific T cell responses, and promotes cures in multiple syngeneic tumor models with minimal systemic side effects.