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. ROS generated 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.
Mengzhen Wang, Yuan Huang, Fangmin Chen et al.· Journal of Controlled Releas...· 0 citations
ConspectusThe emerging advance of targeted protein degradation (TPD) technology offers a novel option for protein modulation, ensuring a more durable and precise therapeutic impact for cancer management. While promising, complete degradation of the proteins of interest (POIs) in both pathological and normal tissues may cause severe side effects. Furthermore, insufficient accumulation of the protein degraders at the target tissues also limits the clinical translation of TPD. It remains an unmet need to achieve spatiotemporally tunable degradation of the POI at the tumor lesion. In recent years, our group has extensively exploited the potential of the stimuli-activatable TPD technology for precise cancer therapy. The stimuli-activatable protein degraders were rationally designed for achieving tumor-specific enrichment in vivo to maximize their therapeutic effects while minimizing the side effects. Several kinds of stimuli-labile prodrugs of the proteolysis targeting chimeras (PROTACs) were rationally designed for restoring their protein degradation functions with the endogenous or exogenous stimulus of tumor while remaining "silent" elsewhere, resulting in precise therapies and reduced side effects. Leveraging the advantages of nanomedicine delivery systems, several kinds of tumor acidity and enzymatic-activatable nanodegraders were developed to achieve tumor-targeted protein degrader distribution and POI degradation. In particular, photothermally activatable protein degraders were developed to perform spatiotemporally controllable degradation of various POIs.In this Account, we systematically summarize recent advances from our group regarding the rational design of stimuli-activatable protein degraders, and strategically outline the "when and how" of integrating these degraders with nanomedicine platforms to tailor precise cancer therapy. We discuss the crucial role of the tumor microenvironment-responsive moieties for stimuli-triggered degradation of both intracellular and membrane POIs, highlighting the distinct design rationale for their respective prodrugs. Furthermore, we summarize our advances of strategic integration of the TPD technology with nanomedicine to augment the therapeutic outcomes of phototherapy, radiotherapy, chemotherapy, and immunotherapy of solid tumors. It is envisaged that the tumor microenvironment-activatable protein degradation approaches will achieve tumor-specific protein degradation and precision therapy, thereby facilitating the clinical application of TPD. By outlining optimized design strategies and future challenges, this Account aims to serve as a roadmap for researchers seeking to develop next-generation activatable TPD technologies that are modular, functionally versatile, and translatable.
Jing Gao, Yi Lai, Bo Hou et al.· Accounts of Chemical Researc...· 0 citations