Tumor immunotherapy can stimulate or augment the immune system of the host, thereby eliciting a targeted immune response against the tumor that can impede its proliferation. In comparison to traditional tumor therapies, immunotherapy offers heightened levels of specificity, diminished adverse effects, and sustained therapeutic outcomes [1,2]. Tumor antigen-specific T cells play a crucial role in antitumor immune response [3]. Unfortunately, only a minority of patients benefit from immunotherapy, probably because of the immune suppressive tumor microenvironment (TME) and insufficient endogenous antitumor T cells response [[4], [5], [6]]. Activation of innate immunity in tumor can promote the initiation and infiltration of antigen-specific T cells [7,8]. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is a major innate immune pathway involved in tumor immunity. It induces the production of type I interferon (IFN-I) and pro-inflammatory cytokines, promotes the maturation of dendrite cells (DCs), increases the infiltration of antigen-specific T cells, and coordinates the innate and adaptive immune responses [[9], [10], [11], [12], [13], [14]]. Thus, activating the cGAS-STING pathway represents a promising strategy for enhancing tumor immunotherapy.

To date, several STING agonists have shown encouraging effects in preclinical studies, including natural cyclic dinucleotides (CDNs) and synthetic small molecule agonists [15,16]. Nevertheless, the therapeutic efficacy of these STING agonists is often compromised by issues such as metabolic instability, limited cellular permeability, and inadequate pharmacokinetic properties, which hinder their further clinical translation [[17], [18], [19]]. More importantly, the activation of the cGAS-STING pathway requires a certain concentration of tumor-derived DNA, as cytoplasmic DNA serves as a STING signal initiator that can be detected by cGAS [7,20]. Therefore, it is imperative to select appropriate STING agonists and devise immunotherapy strategies that can specifically and efficiently activate the cGAS-STING pathway at the tumor site. Manganese (Mn2+ in general cases), as a nutritional trace element, plays multiple roles in tumor therapy. On the one hand, Mn2+, which serves as a STING agonist, activates the cGAS-STING pathway by increasing the sensitivity of cGAS to cytoplasmic DNA detection and promoting the STING cascade reaction [21]. On the other hand, Mn2+ can convert endogenous hydrogen peroxide (H2O2) to cytotoxic hydroxyl radical (·OH) through a Fenton-like reaction, kill tumors through chemodynamic therapy (CDT) [[22], [23], [24], [25], [26]], and further induce immunogenic cell death (ICD) [27,28]. Notably, traditional treatments such as chemotherapy and radiotherapy can sensitize the Mn2+-mediated cGAS-STING pathway by promoting intracellular DNA leakage [[29], [30], [31]]. Therefore, fully utilizing the Mn2+ properties and combining them with chemotherapy to sensitize the cGAS-STING pathway, could synergistically promote the maturation of DCs and the production of antigen-specific T cells in a multifaceted way, thereby inducing a strong antitumor immune response.

However, the direct injection of Mn2+ fails to elicit an efficient immune response due to its non-specific distribution and rapid metabolism of free Mn2+. The development of systemically administered nanotheranostics may overcome pharmacokinetic limitations and enhance drug delivery [[32], [33], [34]]. Metal coordination polymers are rising multifunctional nanomaterials formed by the coordination of metal ions and organic ligands, which are characterized by a simple and rapid coordination process, easy surface modification, high drug-carrying capacity, and smart responsive drug release, showing high application prospects in the field of tumor therapy [[35], [36], [37]]. Manganese-based metal coordination nanomaterials such as radiosensitizer-based metal-phenolic networks (DSPM) [29] and CDN‑manganese particles (CMPs) [38] have been developed for activating the cGAS-STING pathway, demonstrating the potential of manganese-based nanomaterials in tumor immunotherapy.

In this study, we presented a promising therapeutic strategy to enhance the Mn2+-mediated immune response by synergistically potentiating the cGAS-STING pathway and promoting ICD effect (Scheme 1). We have chosen gemcitabine (Gem), a structurally unique drug, as a model to coordinate with Mn2+ to form metal coordination nanotheranostics (MGP) through a coordination-driven strategy in the presence of polyvinyl pyrrolidone (PVP). The mechanism of action of MGP was based on the exceptional synergy between Gem and Mn2+. PVP functioned as a dispersant and protector to obtain the nanoscale metal coordination nanotheranostic. Notably, after modification with polyethylene glycol derivatives (DSPE-PEG), MGP exhibited remarkable stability and effectively accumulated at the tumor site via the enhanced permeability and retention (EPR) effect. Once internalized by cancer cells, the released Mn2+ could enhance the activation of the cGAS-STING pathway aided by Gem-induced damaged DNA. Simultaneously, Mn2+ exerted cytotoxic effects by producing reactive oxygen species (ROS), leading to the ICD effect. Such a combined therapeutic strategy sensitized the activation of the cGAS-STING pathway, promoted the DCs maturation and antigen-specific T cells infiltration in a comprehensive manner, and demonstrated prominent antitumor effects in vitro and in vivo with the aid of anti-PD-1. Overall, MGP offered a new platform for the systemic treatment of cancer, and this work underscored the enormous potential of metal coordination nanotheranostics for metalloimmunotherapy.