Nanomedicine Approaches to Overcome Immune Escape in Cold Tumors: Mechanisms and Future Directions

Abstract

The immunosuppressive microenvironment of cold tumors has become a major challenge in tumor therapy due to the lack of T-cell infiltration and insufficient antigen-presenting capacity. This paper systematically reveals its core escape mechanisms, including aberrant activation of immune checkpoint molecules (PD-L1/CTLA-4) leading to T-cell depletion, and synergistic suppression of anti-tumor immunity by metabolic reprogramming and epigenetic dysregulation. Targeting dense matrices and multiple immunosuppressive barriers, nanomedicine achieves precise breakthroughs through functionalized carriers. For example, liposome-targeted delivery of STING agonists reshapes antigen presentation, individualized mRNA vaccines combined with immune checkpoint inhibitors (ICIs) significantly prolong survival, and photo-thermo-responsive gold nanoparticles induce immunogenic death and enhance remission rate. However, clinical translation still faces three major bottlenecks-inefficient tumor-targeted delivery, post-treatment immunosuppression rebound and insufficient material biocompatibility. Future research needs to integrate degradable smart carriers, artificial intelligence (AI)-driven antigen screening and multimodal therapeutic strategies to overcome toxicity limitations and maximize therapeutic efficacy, and ultimately promote the paradigm shift of cold tumors from “immune indifference” to “therapeutic sensitivity”.