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The tumor microenvironment is closely linked to the initiation, promotion, and progression of solid tumors. Among its constitutions, immunologic cells emerge as critical players, facilitating immune evasion and tumor progression. Apart from their indirect impact on anti-tumor immunity, immunocytes directly influence neoplastic cells, either bolstering or impeding tumor advancement. However, current therapeutic modalities aimed at alleviating immunosuppression from regulatory cells on effector immune cell populations may not consistently yield satisfactory results in various solid tumors, such as breast carcinoma, colorectal cancer, etc. Therefore, this review outlines and summarizes the direct, dualistic effects of immunocytes such as T cells, innate lymphoid cells, B cells, eosinophils, and tumor-associated macrophages on tumor cells within the tumor microenvironment. The review also delves into the underlying mechanisms involved and presents the outcomes of clinical trials based on these direct effects, aiming to propose innovative and efficacious therapeutic strategies for addressing solid tumors.

Abstract Cisplatin (DDP) is a prevalent chemotherapeutic agent used in tumor therapy, yet DDP-induced acute kidney injury (AKI) severely limits its clinical application. Antioxidants as reactive oxygen species (ROS) scavengers can circumvent this adverse effect while leading to the decrease of efficacy to tumor. Herein, we report ultrasmall ruthenium nanoparticles (URNPs) as switchable ROS scavengers/generators to alleviate DDP-induced AKI and improve its therapeutic efficacy. In the physiological environment of the kidney, URNPs mimic multi-enzyme activities, such as superoxide dismutase and catalase, effectively protecting the renal cell and tissue by down-regulating the increased ROS level caused by DDP and alleviating AKI. Specifically, URNPs are oxidized by high levels of H2O2 in the tumor microenvironment (TME), resulting in the generation of oxygen vacancies and Ru3+/Ru4+ ions. This unique structure transformation endows URNPs to generate singlet oxygen (1O2) under laser irradiation and hydroxyl radicals (∙OH) through a Fenton-like reaction in tumor cell and tissue. The simultaneous generation of multifarious ROS effectively improves the efficacy of DDP in vitro and in vivo. This TME-responsive ROS scavenger/generator acts as an adjuvant therapeutic agent to minimize side effects and improve the efficacy of chemotherapy drugs, providing a new avenue to chemotherapy and facilitating clinical tumor therapy. Graphical Abstract