Melanoma is a extremely aggressive malignancy with an growing international incidence, characterised by speedy development and a powerful propensity for distant metastasis, usually resulting in poor medical outcomes, particularly in superior phases the place 5-year survival charges are considerably decreased [1], [2]. Typical therapies, together with surgical procedure, radiotherapy, and chemotherapy, have proven restricted efficacy in superior melanoma, leading to excessive recurrence charges [3], [4], [5]. Not too long ago, immunotherapy has reworked melanoma remedy by leveraging the affected person’s immune system to particularly goal tumor cells, resulting in promising therapeutic outcomes [6]. Nevertheless, vital challenges resembling immune evasion, remedy resistance, and low response charges persist, with solely 10–40 % of sufferers deriving substantial profit from present therapies [7]. A serious bottleneck lies within the inefficiency of antigen presentation, which is crucial for strong tumor-specific T-cell activation and sturdy antitumor immunity. Addressing this limitation requires modern methods that allow antigen presentation, successfully coordinating a number of immune processes for superior therapeutic outcomes.
At the moment, a number of approaches have been explored to reinforce the effectivity of antigen presentation in melanoma immunotherapy [8]. Dendritic cells (DCs), specifically, have attracted appreciable consideration because of their distinctive means to seize, course of, and current tumor-associated antigens (TAAs) with excessive constancy, thereby orchestrating each innate and adaptive immune responses [9], [10]. As probably the most potent antigen-presenting cells (APCs), DCs play a central position in orchestrating each innate and adaptive immune responses inside the tumor microenvironment (TME) [11], [12]. By the seize, processing, and presentation of tumor-associated antigens (TAAs) to CD4+ and CD8+ T cells through Main Histocompatibility Advanced (MHC) class II and sophistication I molecules, respectively, DCs set off highly effective antitumor immune responses [13]. Along with antigen presentation, dendritic cells (DCs) act as immune sentinels able to detecting pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs), and subsequently enter the maturation stage. This course of is characterised by the upregulation of co-stimulatory molecules resembling CD80 and CD86, the secretion of pro-inflammatory cytokines like interleukin-12 (IL-12) and tumor necrosis factor-alpha (TNF-α), and the expression of the chemokine receptor CCR7, which facilitates their migration to secondary lymphoid organs. Within the lymph nodes, mature dendritic cells provoke naive T cells and information the polarization of CD4⁺ T cells in accordance with the cytokine milieu. In the meantime, they activate cytotoxic T lymphocytes by cross-presenting exogenous antigens by way of main histocompatibility complicated class I (MHC I). Quite a few therapeutic methods, together with most cancers vaccines, immunoadjuvants, and stimulators of interferon genes (STING) agonists, goal to harness or improve the features of dendritic cells. These approaches search to interrupt immune tolerance and overcome tumor-induced immunosuppression[14], [15]. Ex vivo-engineered DC cells, for example, sidestep the immunosuppressive TME and straight current antigens to T cells for fast activation [16], [17]. Alternatively, strategies are designed to that search to advertise in-situ DCs performance straight on the tumor web site, overcoming the constraints of ex vivo-cells [18], [19]. Current research have additional superior these methods by integrating personalised neoantigen supply programs that particularly goal dendritic cells (DCs). This technique has proven outstanding potential in boosting antigen uptake and T cell priming, thereby paving the best way for the event of personalised most cancers vaccines [20]. In the meantime, reprogramming the tumor microenvironment has emerged as an efficient method. It will probably improve ferroptosis and set off the activation of in – situ DCs, initiating the innate immune response and serving to to beat the drug resistance of refractory tumors. These analysis findings collectively spotlight the pressing want for modern platforms. Such platforms mustn’t solely promote dendritic cell maturation and antigen presentation but additionally regulate the immunosuppressive tumor microenvironment, in the end resulting in improved therapeutic outcomes [21]. Due to this fact, the event of superior dendritic cell – centered therapeutic methods that may concurrently surmount the bottlenecks in antigen presentation and reshape the tumor microenvironment stays of utmost significance for totally harnessing the immunotherapeutic potential of dendritic cells in melanoma remedy. Regardless of these advances, boundaries resembling inefficient TAAs loading and restricted antigen presentation pathways proceed to hamper therapeutic efficacy, underscoring the pressing want for modern platforms that bolster DC maturation, optimize TAA presentation, and in the end improve medical outcomes [22], [23]. Due to this fact, growing superior DC-centered approaches that surmount these antigen-presentation bottlenecks stays essential to completely leverage DCs’ immunotherapeutic potential in melanoma remedy.
For an efficient antitumor immune response, DCs should transition from an immature state, characterised by excessive phagocytic exercise, to a mature state, the place they will effectively seize and current TAAs to cytotoxic T lymphocytes (CTLs) [24], [25]. Nevertheless, reaching strong DC maturation stays a serious impediment within the growth of potent DC-based methods [26], [27]. Our earlier research have proven that Mn2+ ions can successfully stimulate each innate and adaptive immune responses [28]. This mechanism includes Mn2+ launch from nanovesicles within the TME, which prompts the cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) pathway and stimulates STING signaling, selling the secretion of pro-inflammatory cytokines that assist DC maturation and migration [29], [30], [31], [32]. Consequently, Mn2⁺-based STING agonists provide appreciable promise in augmenting DC-centric immunotherapy. Particularly, manganese dioxide (MnO2) nanomaterials, function environment friendly Mn2+ reservoirs, releasing it in a managed method inside the TME to maintain STING activation [33], [34]. Such activation triggers the cGAS-STING pathway, thereby producing inflammatory cytokines that gasoline additional DC maturation [35], [36], [37]. However, guaranteeing that mature DCs successfully seize and current clinically related TAAs stays an ongoing problem.
In the meantime, immunogenic cell dying (ICD) has emerged as a potent mechanism for TAAs launch and strong antigen presentation [38], [39], [40], [41]. Amongst varied ICD inducers, platinum-based chemotherapeutics are particularly efficient at upsetting ICD by binding to intracellular double-stranded DNA (dsDNA), thereby releasing damage-associated molecular patterns (DAMPs) and TAAs [42]. As an example, ultra-small Pt nanoparticles can constantly launch Pt²⁺ ions inside the tumor microenvironment, which inflicting injury to each mitochondrial and nuclear DNA. This initiates immunogenic cell dying (ICD) and additional prompts the cGAS-STING pathway, thereby enhancing antitumor immunity [43], [44]. This sturdy immunostimulatory impact has been validated in a number of in each in vitro and in vivo fashions [45], [46]. The combination of those complementary immunostimulatory mechanisms right into a single nanoplatform affords a pleiotropic technique to concurrently improve DC maturation, antigen uptake, and T-cell priming, driving strong antitumor immunity.
Herein, we devised a platinum-manganese nanohybrid (Pt@MnO2) that integrates the properties of a STING agonist and an ICD inducer (Scheme 1a). When incubated with B16-OVA melanoma cells, this nanohybrid concurrently releases Mn2+, a potent cGAS–STING activator, and Pt2+, which induces ICD. These twin indicators stimulate the secretion of inflammatory cytokines and tumor-associated antigens (TAAs), making a cytokine- and TAAs-enriched setting. Immature DCs cultured on this setting endure maturation and successfully uptake TAAs.
To additional exploit these immunostimulatory mechanisms, we engineered a multifunctional nanohybrid by coating Pt@MnO2 with cell membranes derived from antigen-enriched mature DCs mediated by Pt@MnO2, thus forming PM@DCm (Scheme 1a). The Pt@MnO2 core acts dually as a STING agonist and ICD inducer, making a TAAs- and cytokine-enriched setting that facilitates in-situ DC maturation, environment friendly antigen uptake, and subsequent T-cell activation. Concurrently, the coating of the mature dendritic cell (DC) membrane not solely maintains its dendritic construction, which is supported by the multi-spiked morphology of Pt@MnO2, but additionally preserves the exercise of essential floor molecules resembling main histocompatibility complicated class I, CD80, CD86, and CCR7. These molecules are essential for antigen presentation and co-stimulatory sign transduction, enabling PM@DCm to imitate mature DCs and straight cross-present tumor-associated antigens (TAAs) to prime cytotoxic T cells. These parts can successfully provoke naive T cells and activate cytotoxic T lymphocytes (CTLs), serving as a bridge between innate immunity and adaptive immunity. This synergistic design ensures pleiotropic antigen presentation, culminating in enhanced antitumor immunity. Consequently, the PM@DCm demonstrates substantial antitumor results in vivo, notably in tumor progress inhibition, metastasis prevention, and prophylactic intervention (Scheme 1b). Total, this research underscores the pleiotropic antigen-presenting capability of the PM@DCm nanohybrids, which offers a promising technique for enhanced immunotherapy and precision drugs.
