The design of activatable photosensitizers and applications in precision immunomodulation

As a non-invasive and spatiotemporally controllable therapeutic strategy, photodynamic therapy (PDT) exhibits distinct advantages in cancer treatment. However, conventional photosensitizers often trigger off-target toxicity due to insufficient tumor-targeting ability, and their uncontrollable activation at non-lesion sites severely compromises therapeutic precision and immunomodulatory potential. Activatable photosensitizers achieve site-specific activation by responding to endogenous tumor signals or exogenous physical stimuli, enabling the selective generation of reactive oxygen species (ROS) in tumor tissues. The generated ROS not only induce tumor cell apoptosis but also modulate the immune system through multiple pathways, including the induction of immunogenic cell death (ICD), activation of the stimulator of interferon genes (STING) pathway, and remodeling of the immunosuppressive tumor microenvironment. This review systematically elaborates on the molecular design principles of activatable photosensitizers and their recent advances in precise immunomodulation for cancer therapy. From the perspective of molecular design, we focus on smart responsive systems that target tumor endogenous signals (e.g., enzymes, ROS, pH, glutathione) and exogenous physical stimuli (e.g., light, ultrasound, X-ray), aiming to enhance the specific activation and accumulation of photosensitizers in tumor sites. In terms of immunomodulation, we delve into the underlying mechanisms by which activatable photosensitizers synergistically potentiate anti-tumor immune responses. Finally, we discuss current challenges, such as tumor microenvironment heterogeneity and inadequate deep tissue penetration, while outlining future directions, including multi-stimuli synergistic activation, structural optimization, and mechanistic elucidation. This review aims to provide valuable insights for advancing activatable photosensitizer-mediated precision immuno-oncology.