TNFR2-targeted nanoparticles for regulatory T-cell modulation in cancer immunotherapy: a narrative review

Cancer immunotherapy has fundamentally transformed the therapeutic landscape of multiple malignancies, particularly through immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1) axis and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). However, the clinical efficacy of these agents remains limited in many patients due to primary or acquired resistance and treatment-associated immune-related adverse events (irAEs). Among emerging immunoregulatory targets, tumor necrosis factor receptor 2 (TNFR2) has attracted increasing attention owing to its preferential overexpression on highly suppressive intratumoral regulatory T cells (Tregs), which play a crucial role in immune evasion, therapeutic resistance, and unfavorable clinical outcomes across diverse malignancies. Although conventional TNFR2-targeting approaches, including monoclonal antibodies and small-molecule inhibitors, have demonstrated promising biological activity, their broader clinical translation is hindered by inadequate tumor penetration, systemic toxicity, off-target effects, and limited selectivity toward TNFR2+ immunosuppressive cell populations within the tumor microenvironment (TME). Nanoparticle-based delivery systems offer a promising platform to address these challenges by improving pharmacokinetic stability, enhancing tumor-selective accumulation, enabling TNFR2-targeting surface functionalization, and facilitating controlled payload release within the TME. In this narrative review, we summarize the molecular and immunological roles of TNFR2, examine the contribution of the TNFR2-Treg axis to tumor immune escape, and discuss current nanoparticle engineering strategies for TNFR2-directed therapy. We also evaluate emerging preclinical evidence, key translational challenges, and future perspectives for TNFR2-targeted nanomedicine in cancer immunotherapy.