Research groups of Professors Weiqi Zhang, Haiyan Xu and Lin Wang from the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, reported a positively-charged dextran nano-photosensitizer (p-Dex PS) facilitates tumor-associated macrophage (TAM)-mediated delivery and sublethal light-induced metabolic reprogramming, which boosts the TAM polarization and subsequently the anticancer immune effects.

Background
Photodynamic therapy (PDT) has emerged as a promising clinical approach for tumor treatment, due to its noninvasiveness and potential to stimulate the antitumor immunity. However, its widespread application confronts multiple challenges, including the limitations of most photosensitizers as lipophilic molecules with poor tumor-targeting capability, combined with the progressive light absorption and scattering effects in biological tissues, which collectively result in rapid attenuation of PDT efficacy in deep-seated tumor. Currently, there is still a significant need for a new strategy that specifically delivers photosensitizers to tumor, overcomes the limited light penetration depth inherent to PDT and enhances the anti-tumor immune activation.

Key Findings
Considering that TAMs play a pivotal role in tumor immune microenvironment, the research team realized a superior anticancer PDT efficacy based on a developed p-Dex PS, unveiled the mechanisms of TAM-mediated delivery and the subsequent elicitation of anticancer immune response. The p-Dex PS engulfed by TAMs can be efficiently transported to tumor cells as evidenced by using both the co-culture of tumoral and macrophagic cells in vitro and the murine breast tumor model in vivo, which suggests the role of TAMs as depots for photosensitizers delivery within the tumor. Moreover, this TAM-mediated targeting p-Dex PS induces metabolic reprogramming and polarization of TAMs under a sublethal light stimulation, consequently triggering robust anti-tumor immune response and potentiating PDT ablation of deep-seated tumor. This innovative strategy overcomes the challenge of limited therapeutic efficacy in conventional PDT, establishing a practicable and facile paradigm for deep-tumor therapy.
DOI：10.1093/procel/pwaf064