Nanoplatform-Mediated Remodeling of the Immune Microenvironment in Renal Cell Carcinoma

Abstract

Abstract Renal cell carcinoma (RCC) is a highly immunogenic malignancy, and immune checkpoint inhibitor-based regimens have substantially improved clinical outcomes. However, primary resistance, acquired resistance, interpatient heterogeneity, and treatment-related systemic toxicity continue to limit therapeutic efficacy. Immune evasion in RCC can be summarized into three interconnected levels: defective immune priming and checkpoint-mediated immunosuppression; vascular-metabolic barriers that impede immune-cell infiltration and effector function; and a suppressive immune microenvironment shaped by myeloid cells, regulatory lymphocytes, cytokines, and extracellular vesicles. Together, these barriers impair effector-cell function and promote T-cell exhaustion. Nanodelivery platforms provide new opportunities to overcome these multistage immunosuppressive constraints through programmable payload loading, spatiotemporally controlled local delivery, and material-enabled modulation of the tumor microenvironment. Based on this multilevel immune-evasion framework, this review organizes current evidence and systematically discusses representative intervention strategies, including restoration of antigen presentation and innate immune sensing, maintenance of effector-cell activation, remodeling of the vascular–metabolic microenvironment, and reprogramming of suppressive immune networks. We further compare the advantages and limitations of lipid-based, polymeric, and inorganic nanoplatforms in terms of payload compatibility, release control, intrinsic physicochemical activity, biosafety, manufacturability, and clinical translatability, and emphasize that therapeutic components should achieve mechanistically grounded synergy rather than simple combination. Although current studies have demonstrated therapeutic potential, RCC nano-immunotherapy remains largely at the preclinical stage and is constrained by limited model translatability, heterogeneous tumor delivery, uncertain long-term safety, manufacturing complexity, and the lack of standardized evaluation criteria. Future efforts should prioritize structurally simplified, mechanistically defined, tumor-microenvironment-responsive platforms, together with biomarker-guided patient stratification and standardized evaluation systems, to facilitate the translation of RCC nano-immunotherapy into reproducible treatment strategies with clear clinical benefit.