Advantages of targeting the tumor immune microenvironment over blocking immune checkpoint in cancer immunotherapy

Abstract

Despite great success in cancer immunotherapy, immune checkpoint-targeting drugs are not the most popular weapon in the armory of cancer therapy. Accumulating evidence suggests that the tumor immune microenvironment plays a critical role in anti-cancer immunity, which may result in immune checkpoint blockade therapy being ineffective, in addition to other novel immunotherapies in cancer patients. In the present review, we discuss the deficiencies of current cancer immunotherapies. More importantly, we highlight the critical role of tumor immune microenvironment regulators in tumor immune surveillance, immunological evasion, and the potential for their further translation into clinical practice. Based on their general targetability in clinical therapy, we believe that tumor immune microenvironment regulators are promising cancer immunotherapeutic targets. Targeting the tumor immune microenvironment, alone or in combination with immune checkpoint-targeting drugs, might benefit cancer patients in the future.

Fig. 1

Hallmarks of an immunosuppressive tumor microenvironment. Six hallmarks, including heterogeneity of constitution, lack of tumor antigen, defect of antigen-presenting cell, impairment of T-cell infiltration, activation of an immunosuppressive signaling pathway, and enhancement of immunosuppressive metabolism co-contribute to an immunosuppressive tumor microenvironment

Fig. 2

Construction of TIME. During tumorigenesis and progression, a variety of cells, including but not limited to macrophage, DC, neutrophil, B cell, T cell, and CAF, are recruited to the surrounding microenvironment of tumor cells, co-constituting the TIME together with the ECM in addition to other elements

Fig. 3

Metabolic regulation of tumor microenvironment for T-cell energy. The high rate of aerobic glycolysis in tumor cells and CAFs deprives immune cells of nutrients that are critical for their physiological function, meanwhile causing increased lactate production, which leads to tumor microenvironment acidification and immunosuppression

Fig. 4

Development and progression of cancer immunotherapeutic strategies. The first-generation of cancer immunotherapy, including but not limited to immunostimulatory cytokines, aimed to generally activate the immune system, so as to promote a concomitant antitumor response. The second-generation of cancer immunotherapy, including but not limited to ICP inhibitors, ICD inducers and CAR-T cells, aimed to block specific immunosuppressive molecules, induce specific cellular processes, or target-specific tumor cells, so as to cause a relatively manageable antitumor response. The third generation of cancer immunotherapy, including but not limited to the co-targeting of ICP and TIME, aimed to jointly inhibit multiple aspects of negative immune regulation, so as to mount an effective and safe antitumor response