Employing epigenetic protein degradation techniques to block CCL5-mediated photodynamic therapy via a programmed delivery platform.

Despite the significant potential of photodynamic therapy (PDT) in cancer treatment, further refinement is needed to address challenges such as poor tumor-specific accumulation of photosensitizers and the development of therapeutic resistance, which may be regulated by epigenetics. Here, a novel tumor microenvironment-responsive delivery platform was developed to co-deliver epigenetic protein degraders and photosensitizers, aiming to block the relevant regulatory mechanisms and enhance the effectiveness of combination therapy. Benefiting from the targeting ability, pH-triggered charge reversal, and intracellular glutathione (GSH)-responsive release, the delivery platform exhibited enhanced tumor accumulation and therapeutic effects. The mechanism of action revealed that the precise accumulation and release of drugs via the tumor-orchestrated delivery system not only regulated cell growth and immune activation, but also inhibited the expression of tumor immune escape molecules (PDL1 and CD47) and M2 macrophage polarization, significantly increasing the anti-breast cancer and anti-melanoma effects of PDT in the presence of an epigenetic modifier. More importantly, we found for the first time that photodynamic therapy can generate therapeutic resistance through the upregulation of CCL5, and confirmed that this resistance can be reduced by the epigenetic degradation of bromodomain-containing protein 4 (BRD4). These findings underscore the potential of integrating PDT with epigenetic protein degraders through a programmed delivery platform, offering a promising strategy for improving cancer treatment outcomes.