Redox modulation with a perfluorocarbon nanoparticle to reverse Treg-mediated immunosuppression and enhance anti-tumor immunity

Immunotherapy evokes body's own immune system to discover and destroy cancer cells, which provides effective ways in treating several types of cancer [1]. With in-depth study of tumor immunology, anti-tumor immunotherapy is booming in both preclinical and clinical research, which is expected to achieve new breakthroughs and become the mainstream method of anti-tumor treatment [2,3]. Despite significant progress in the treatment of certain types of tumors, most immunotherapies are still ineffective for many patients, and the response rate remains in a low condition [4]. Mechanism study reveals that the immunosuppression in the TME is always the driving force behind the poor effect of preclinical and clinical immunotherapy [5]. Typically, immunosuppressive TME constructed by regulatory T cells (Tregs) and related cytokines provides a protective barrier for tumor growth and metastasis, which is the bottleneck of anti-tumor immunotherapy [6]. Tregs can inhibit the maturation of dendritic cells (DCs), reduce the activity of effector T cells, and prevent them from entering TME by secreting immunosuppressive cytokines such as transforming growth factor-β (TGF-β), thus resulting in immune desert [7,8]. Overcoming Treg mediated immunosuppression and developing corresponding treatment strategies are the key to break through the anti-tumor immunosuppressive barrier [9].

The current clinical reports point out that chemical drugs such as gemcitabine can kill Tregs by inhibiting the gene synthesis, thereby weakening the immunosuppressive TME [10]. However, the systemic toxicity of chemotherapy drugs greatly limits their clinical application and reduces the life quality of patients. Alternatively, daclizumab can block the interleukin-2 signaling pathway by binding to CD25, which leads to cell death of Tregs [11]. Notably, Tregs also play a role in maintaining immune balance in the body. Targeted killing of systemic Tregs could easily break the balance of the body's immune system, thus inducing autoimmune diseases and systemic inflammation [12]. Moreover, Tregs still have immunosuppressive effects after apoptosis by specific metabolic behavior. Dying Tregs quickly convert the released adenosine triphosphate (ATP) to adenosines, which subsequently bind to receptors on the surface of T cells and inactive them [13]. In order to reverse the immunosuppression and make more cancer patients benefit from immunotherapy, it is better to develop treatment strategies to prevent Tregs from migrating to the TME or restrict the immunosuppressive function of Tregs in the follow-up research rather than killing Tregs directly [14,15].

The announcement of the Nobel Prize in physiology and medicine in 2019 brings oxygen and redox metabolism up to the center of the stage of life science [16]. Their results provides how oxygen levels affect cell metabolism and physiological functions, which shapes the new strategies to fight anemia [17], cancer [18,19] and many other diseases [20]. Notably, recent research has discovered an immune metabolism mechanism, that is, glutathione (GSH) is essential to maintain the Foxp3 expression and immunosuppressive function of Tregs. Under the action of this mechanism, the elimination of GSH can overcome the immunosuppression in the TME [21]. Moreover, the hypoxic state of the TME can recruit Tregs infiltration, and hypoxia inducible factor-1 (HIF-1α) can also induce the expression of Fxop3 and promote Tregs proliferation, contributing to the immunosuppression of the TME [22]. Therefore, overcoming Treg mediated immunosuppression from the perspective of redox metabolism modulation in the TME, has become the key to improve the response rate of cancer immunotherapy.

Here, we developed a fluorine assembled nano-formulation to overcome the Treg mediated immunosuppression by redox regulation to restrict the Treg function and infiltration. In view of the extremely hypoxic condition in immunosuppressive tumors, the perfluorocarbon (PFC) in the nano-formulation contains sufficient oxygen can relieve the hypoxia in the TME thus reducing the proliferation and infiltration of Tregs [23] (Fig. 1A). Moreover, the chemical prodrug (M) released under laser irradiation can efficiently down-regulate the GSH content [24,25], and reduce the expression of Foxp3 in Tregs thus reversing its immunosuppressive function (Fig. 1B). In addition, the downregulation of GSH and upregulation of oxygen work together with the photodynamic therapy to induce potent immunogenic cell death thus promoting the maturation of DCs and activation of effector T cells. Meanwhile, the regulation of HIF-1α and GSH releases the shackles of Treg induced immunosuppression, to completely awaken the anti-tumor immunity. In different tumor models, our results demonstrated that redox regulatory treatment strategy can boost anti-tumor immunity by restricting the immunosuppressive function of Tregs, showing encouraging potential in breaking through the treatment bottleneck of immunosuppressive tumors.

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