AbstractcGAS-STING pathway is a key DNA-sensing machinery and emerges as a promising target to overcome the immunoresistance of solid tumors. Here we describe a bovine serum albumin (BSA)/ferritin-based nanoagonist incorporating manganese (II) ions and β-lapachone, which cooperatively activates cGAS-STING signaling in dendritic cells (DCs) to elicit robust adaptive antitumor immunity. Mn2+-anchored mannose-modified BSAs and β-lapachone-loaded ferritins are crosslinked to afford bioresponsive protein nanoassemblies, which dissociate into monodispersive protein units in acidic perivascular tumor microenvironment (TME), thus enabling enhanced tumor penetration and spatiotemporally controlled Mn2+ and β-lapachone delivery to DCs and tumor cells, respectively. β-lapachone causes immunogenic tumor cell apoptosis and releases abundant dsDNA into TME, while Mn2+ enhances the sensitivity of cGAS to dsDNA and augments STING signaling to trigger downstream immunostimulatory signals. The cGAS-STING nanoagonist enhances the tumor-specific T cell-mediated immune response against poorly immunogenic solid tumors in vivo, offering a robust approach for immunotherapy in the clinics.

Ferroptosis is anew form of regulated cell death that shows promise for tumor treatment. Most current ferroptosis tumor therapies are based on the intrinsic pathological features of the malignancies,and it would be of clinical significance to develop ferroptosis-inducing strategies with improved tumor specificity and modulability.Here we report ap olydopaminebased nanoplatform (Fe II PDA@LAP-PEG-cRGD) for the efficient loading of Fe 2+ and b-lapachone (LAP), which could readily initiate ferroptosis in tumor cells upon treatment with near-infrared light. PDAn anostructures could generate mild hyperthermia under NIR irritation and trigger the release of the ferroptosis-inducing Fe 2+ ions.T he NIR-actuated photothermal effect would also activate cellular heat shock response and upregulate the downstream NQO1 via HSP70/NQO1 axis to facilitate bioreduction of the concurrently released b-lapachone and enhance intracellular H 2 O 2 formation to promote the Fe 2+-mediated lipid peroxidation.

Radio-immunotherapy exploits the immunostimulatory features of ionizing radiation (IR) to enhance antitumor effects and offers emerging opportunities for treating invasive tumor indications such as melanoma. However, insufficient dose deposition and immunosuppressive microenvironment (TME) of solid tumors limit its efficacy. To address these challenges, a cascade-amplification strategy based on multifunctional fusogenic liposomes (Lip@AUR-ACP-aptPD-L1) was reported. The liposomes were loaded with gold-containing Auranofin (AUR) and inserted with multivariate-gated aptamer assemblies (ACP) and PD-L1 aptamers in the lipid membrane, potentiating melanoma-targeted AUR delivery while transferring ACP onto cell surface through selective membrane fusion. AUR amplified IR-induced immunogenic death of melanoma cells to release antigens and damage-associated molecular patterns such as ATP for triggering adaptive antitumor immunity. AUR-sensitized radiotherapy also upregulated MMP-2 expression that combined with released ATP to cause AND-gate activation of ACP, thus triggering the in-situ release of CpG-based immunoadjuvants for stimulating dendritic cell-mediated T cell priming. Furthermore, AUR inhibited tumor-intrinsic ERK1/2-HIF-1α-VEGF signaling to suppress infiltration of immunosuppressive cells for fostering an anti-tumorigenic TME. This study offers an approach for solid tumor treatment in the clinics.