Current cancer immunotherapy primarily focuses on the activation of T cells to initiate an immune response. The sustained efficacy of this approach in battling cancer predominantly relies on the cancer-immunity cycle. This intricate cycle encapsulates a series of sequential events, wherein the immune system identifies and eradicates cancer cells. This process entails pivotal stages such as the liberation of tumor antigens, presentation of antigens, activation of T cells, their subsequent recruitment and infiltration into the tumor microenvironment, culminating in the elimination of cancer cells through the action of activated T cells [1,2]. Impairing any of these steps may potentially compromise the tumor-specific immune response. To improve the outcomes of antitumor immunotherapy, researchers are delving into the realm of combination therapies that target multiple phases within the cancer-immunity cycle. These multifaceted approaches hold great promise in bolstering the body's capacity to effectively combat cancer.

Despite the extensive exploration of nano-based delivery systems to overcome hurdles in the cancer-immunity cycle, their effectiveness remains hampered by challenges, particularly concerning limited immunogenicity and potential systemic toxicity [[3], [4], [5]]. In contrast, hydrogels, characterized by their crosslinked polymeric network, have gained substantial attention as a delivery system with remarkable encapsulation efficiency and distinctive stimuli-responsive attributes, which hold significant potential for elevating the immune response [3,6,7]. Furthermore, hydrogels demonstrate biocompatibility, biodegradability, and capacity for cell-specific targeting, rendering them an appealing platform for cancer immunotherapy [3,6]. Numerous studies have investigated the potential of hydrogels to enhance the immune response by delivering immunostimulants in a regulated and enduring manner, thereby mitigating the risk of off-target effects. This controlled delivery strategy creates an environment that fosters immune cell activation and infiltration within the tumor locale [3]. Consequently, hydrogel-based delivery systems hold great promise in advancing cancer immunotherapy due to their ability to enhance and modulate the cancer-immunity cycle. By orchestrating the controlled release of immunostimulants and antigens, these delivery systems can effectively amplify the activation and infiltration of immune cells, ultimately enhancing anti-tumor reactions while constraining adverse impacts.

Initiating the cancer-immunity cycle effectively hinges on the availability of adequate antigens, marking the initial critical step for successful cancer immunotherapy. The optimal scenario entails these antigens being adeptly captured by antigen-presenting cells (APCs) and subsequently presented to T cells [2]. Nonetheless, various factors may impede this process, resulting in diminished T cell activation. These challenges encompass insufficient antigen content characterized by low immunogenicity, non-specific interactions of dendritic cells (DCs), and the suboptimal presentation efficiency of antigens by DCs to T cells. To overcome these obstacles, researchers have explored the application of whole tumor antigens derived from inactivated autologous or allogenic tumor cells in vitro, a strategy that elevates antigen immunogenicity [3,8]. Furthermore, novel in situ tumor ablation approaches have been devised to induce tumor cell death and subsequent release of tumor antigens in vivo, thereby fostering an in situ autologous tumor antigen reservoir with enhanced immunogenicity [3]. Lymph nodes (LNs) serve as pivotal “base camps” for immune cells, including DCs and T cells [9]. For successful DCs maturation, the presence of antigens and adjuvants is imperative. Toll-like receptor 4 (TLR4) agonists, classical vaccine adjuvants, activate DCs by prompting the expression of surface costimulatory and cytokine signals [10]. The drainage of antigens and adjuvants to LNs facilitates the maturation of DCs population. However, addressing obstacles tied to DCs' antigen presentation to T cells is equally critical, notably the challenges stemming from the diminished expression of TCRs and the restricted formation of IS between DCs and T cells.

Calcium ions (Ca2+) serve as pivotal second messengers in an array of signaling pathways, demonstrating their indispensable role in the formation of immune synapses (IS) [11] and the initiation of TCR signaling [12,13]. Notably, ionomycin, a calcium salt, has proven effective in fostering IS formation between APCs and T cells. This phenomenon facilitates telomere transfer, ultimately instigating enduring immune responses [14]. Building on this knowledge, we propose a localized implantable gel strategy aimed at modulating the cancer-immunity cycle through a triple-step approach (Fig. 1): Step 1, creation of an autologous tumor antigen pool via photothermal ablation, inducing immunogenic cell death (ICD) in the tumor tissue; Step 2, drainage of antigens and adjuvants specifically to LNs enriched with DCs via a nanoparticle size- and charge-driven process; Step 3, promotion of DCs and T cell fusion and antigen presentation by increasing intracellular Ca2+ levels to enhance T cell activation. The implementation of this strategy employs LN-targeted nanoparticles loaded within the gel implant, thereby enabling the concurrent delivery of in situ-generated tumor antigens and adjuvants, thus effectively activating DCs. Subsequently, we explore the potential of intensifying T cell activation by heightening intracellular Ca2+ signaling, a move designed to propel the fusion of DCs and T cells, thereby fortifying the cancer-immunity cycle.