Engineering stimuli-responsive prodrugs to overcome barriers in cancer immunotherapy

Immunotherapy has revolutionized cancer treatment in recent years; however, limited response rates and immune-related adverse effects remain significant challenges. These limitations are mainly due to poor tumor penetration, systemic toxicity, and resistance within the immunosuppressive tumor microenvironment (TME). Stimuli-responsive prodrug nanomedicines have emerged as a promising strategy to address these barriers by enabling site-specific drug activation in response to endogenous (e.g., pH, redox potential, enzymes, hypoxia) or exogenous (e.g., light, ultrasound) triggers. These systems facilitate controlled drug release, minimize premature leakage, and enhance antitumor immune responses through co-delivery of immunomodulators and immunogenic cell death (ICD) inducers. This review summarizes recent advances in the design and application of stimuli-responsive prodrug nanoplatforms for cancer immunotherapy. Common stimuli, activation mechanisms, and nanocarrier strategies aimed at improving tumor targeting, pharmacokinetics, and therapeutic efficacy while reducing systemic toxicity are discussed. Particular attention is given to prodrug systems developed to enhance immune checkpoint inhibitors and other clinically relevant immunotherapeutic approaches through modulation of the TME, induction of ICD, and promotion of immune activation. In addition, current challenges and limitations related to clinical application are discussed, and potential future research directions are briefly highlighted.