The immunosuppressive tumor microenvironment (ITM) and low immunogenicity of tumors greatly limit cancer immunotherapy efficacy. The approach of solely depleting regulatory T cells (Tregs) cannot ameliorate ITM, but possibly worsen it since the produced apoptotic Tregs will activate the A2A signaling pathway and cause more severe immune suppression. To address it, in this work a pH-responsive polymersome (CY/ZM@CS-BPA) based on chondroitin sulfate (CS)-poly(β-amino ester) is rationally developed. In the acidic tumor microenvironment, the tertiary amine groups in the polymersome will reverse from hydrophobic to hydrophilic due to protonation, which leads to the disintegration of nanostructures and the release of cyclophosphamide (CY) and A2A receptor (A2AR) antagonist ZM241385 (ZM). CY can selectively deplete Tregs. Additionally, CY can induce immunogenic cell death (ICD) of tumor cells, which results in the proapoptotic translocation of calreticulin to the cell surface, further initiating the antitumor immune responses. ZM can inhibit the activation of the adenosine A2A pathway, subsequently preventing the differentiation of CD4⁺ T cells into Tregs and enhancing the cytotoxicity of CD8⁺ T cells. As a result, the combination of depleting regulatory T cells and blocking the A2A receptor can enhance cancer immunotherapy efficacy.

As a minimally invasive local cancer therapy, photothermal therapy (PTT) has aroused intensive interests in recent years. However, the therapeutic effect of PTT is still unsatisfying due to the production of heat shock proteins. Combination therapy has been regarded as a promising strategy to enhance therapeutic efficiency. In this study, a novel intelligent protoporphyrin (PpIX)-based polymer nanoplatform is developed for synergistic enhancement of cancer treatment through combined PTT and nitric oxide (NO) therapy. The core of the nanoparticle is composed of closely packed porphyrin-based NO donors and PpIX branches of the block copolymer. The prepared nanoparticles exhibit good photothermal conversion capability and high sensitivity to release NO under light illumination. And the produced high localized temperature and intracellular NO concentration could efficiently inhibit cancer cells both in vitro and in vivo. More important, this therapeutic nanoplatform can fundamentally eliminate the emergence of multidrug resistance and overcome the hypoxia microenvironment in tumors because of the absence of chemotherapeutic drugs and the oxygen-independent process, thus opening up new ideas for multifunctional therapeutic agent design for treatment of multidrug-resistant cancer.