Targeting the Negative Feedback of Adenosine‐A2AR Metabolic Pathway by a Tailored Nanoinhibitor for Photothermal Immunotherapy

Abstract

The metabolite adenosine plays an important immunosuppressive role in the tumor microenvironment (TME) through its ligation with the metabolic checkpoint adenosine 2A receptor (A2AR). Here, an adenosine‐A2AR negative feedback pathway is highlighted during photothermal‐induced immunogenic cell death (ICD). Adenosine, hydrolyzed from ATP, is amplified during the photothermal‐induced ICD process. It is possible to achieve a robust ICD‐based immunotherapy via targeting the adenosine‐A2AR metabolic pathway. In this regard, an A2AR inhibitor‐loaded polydopamine nanocarrier masked by an acid‐sensitive PEG shell is designed to enable tumor‐specific delivery and photothermal‐induced ICD simultaneously. Upon reaching the acidic TME, the PEG shell selectively detaches and exposes the adhesive polydopamine layer, causing the inhibitors to accumulate at the tumor tissue. The accumulated inhibitors attenuate adenosine's metabolically suppressive effect and strengthen the ICD immune response. It occurs through promoting dendritic cell (DC) activation, increasing CD8+ T lymphocyte infiltration, and reducing the myeloid‐derived suppressor cell (MDSC) population. Furthermore, this synergistic therapy significantly regresses the primary tumor, inhibits distal tumor growth, and prevents lung metastasis. The study highlights a strategy to enhance the immunotherapy efficacy of ICD by blocking the metabolic checkpoint A2AR using advanced nanomaterials.

Tumor Metabolism-Rewriting Nanomedicines for Cancer Immunotherapy

“…The strategic utilization of an adenosine receptor blockade has also arisen as a promising strategy to enhance the therapeutic efficacy of cancer immunotherapy. Recently, Liu et al found that the negative feedback pathway involving adenosine and adenosine 2A receptors (A2AR) was significantly enhanced during photothermal-induced ICD . To circumvent this issue, they developed a pH-activatable nanomedicine (PPDAIn) for synergistic photothermal immunometabolic therapy (Table ).…”

“…To circumvent this issue, they developed a pH-activatable nanomedicine (PPDAIn) for synergistic photothermal immunometabolic therapy (Table ). PPDAIn was constructed by loading the A2AR inhibitor (SCH58261) into polydopamine-based nanocarriers, followed by masking with a pH-sheddable PEG layer through reversible conjugation of BA and catechol. Upon arrival at the TME, the tumor acidity triggered the detachment of PEG, leading to exposure of the adhesive polydopamine layer and subsequent release of SCH58261.…”

Hydrogel-guided strategies to stimulate an effective immune response for vaccine-based cancer immunotherapy

“…Similarly, adenosine, hydrolyzed from ATP, is involved in tumor immune evasion by binding with A2A adenosine receptors (A2AR) on the surface of T cells, known as the denosine-A2AR negative feedback pathway ( 130 ). Inhibition of adenosine generation and signaling pathways have been shown to effectively block the denosine-A2AR pathway ( 131 ). Recently, Zhao et al ( 132 ) introduced adenosine deaminase (ADA) into hydrogels, which enabled the catalytic transformation of adenosine (immunosuppressor) into inosine (an immunopotentiator), thus reversing tumor immunosuppression and enhancing antitumor immune responses.…”

Immunosuppressive adenosine-targeted biomaterials for emerging cancer immunotherapy

“…Central to this therapeutic strategy is the synergistic amplification of immunomodulatory effects of adenosine inhibitors with therapies that induce ICD. Either the biomaterial carries chemotherapeutic agents capable of inducing ICD, such as doxorubicin (DOX), oxaliplatin (OXA), and paclitaxel (PTX), or the biomaterial is linked to lightinduced reactivity that triggers ICD (7,(34)(35)(36)41) (Table 1). These treatments will directly kill tumor cells and induce the release of pro-inflammatory ATP and tumor antigens from tumor cells, subsequently initiating a specific antitumor immune response.…”