Stimuli-Responsive Polymeric Nanosystems for Precision Cancer Nanovaccines

ConspectusThe development of appealing cancer vaccines marks a significant advancement in precision cancer immunotherapy. Its core mechanism involves delivering tumor antigens to activate host dendritic cells (DCs), thereby initiating and amplifying specific T-cell immune responses to be capable of recognizing and eliminating cancer cells. However, the clinical efficacy of this approach faces several major challenges, including tumor heterogeneity and immune evasion mechanisms within the tumor immunosuppressive microenvironment (TIME). Furthermore, traditional delivery systems often lack spatiotemporal control and fail to ensure the efficient uptake of antigens and adjuvants by lymph node-resident DCs, thereby limiting the generation of effective immune responses. To address these limitations, cancer nanovaccines have evolved from single-antigen formulations toward systemic remodeling of the TIME. Modern immunotherapies aim to disrupt the local immunosuppressive state of tumors and establish a self-sustaining antitumor immune cycle. However, the nonspecific systemic distribution of immunomodulatory drugs can readily induce immune-related adverse events, prompting the development of powerful delivery systems with targeted and controlled release properties. In recent years, stimuli-responsive polymeric nanosystems have emerged as intelligent nanoplatforms for drug delivery. These nanosystems can be engineered to maintain the structural stability in circulation, accumulate in tumor regions via an enhanced permeability and retention (EPR) effect, and respond to various stimuli at desired sites. Upon TIME-specific signals or exogenous stimuli, these nanostructures undergo conformational changes or degradation, enabling spatiotemporally controlled release of loaded immune agonists, checkpoint inhibitors, or cytokines. This strategy not only significantly enhances the bioavailability of immunomodulators at target sites and reduces systemic toxicities but also enables the sequential codelivery of synergistic therapeutic agents. As a result, the immunotherapy combined with stimuli-responsive polymeric nanosystems can efficiently transform immunologically “cold” tumor into “hot” tumor, ultimately achieving profound and sustained modulation of the antitumor immune responses.This Account highlights recent advances in stimuli-responsive polymeric nanosystems with a particular focus on four pivotal functions in cancer vaccines: First, they can serve as versatile carriers for immunomodulators via diverse nanostructures; second, specific structural motifs within polymers can confer intrinsic adjuvant effects to enhance the activation of the immune system; third, they act as in situ nanovaccines through targeted induction of immunogenic cell death (ICD); last, they can behave as precision regulators of the TIME, converting immunologically “cold” tumor into “hot” tumor. We further provide an in-depth discussion on the design and fabrication of polymeric nanovaccines that are responsive to endogenous stimuli (e.g., pH, redox, and enzyme) and exogenous stimuli (e.g., temperature, light, and ultrasound). Collectively, stimuli-responsive polymeric nanovaccines can hold great promise as next-generation cancer nanovaccines, offering a modular, safe, and effective strategy for personalized treatment.