Advancements in polymer-based drug delivery systems targeting the tumor microenvironment for immunotherapy of triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by high invasiveness, frequent recurrence, and metastasis, along with limited targeted therapeutic options. Despite clinical advances achieved with immune checkpoint inhibitors, poly(ADP-ribose) polymerase (PARP) inhibitors, and antibody-drug conjugates, the complex immunosuppressive tumor microenvironment (TME) of TNBC hinders drug delivery and compromises the efficacy of immunotherapy. Multiple adverse features of the TME, including impaired tumor immunogenicity, dysfunctional antigen presentation, dense extracellular matrix barriers, abundant immunosuppressive cell populations, metabolic reprogramming, hypoxia, and acidification, collectively contribute to immunotherapy resistance. Polymer-based drug delivery systems (PBDS), with tunable physicochemical properties, structural versatility, high drug-loading capacity, and responsiveness to TME-associated stimuli, have emerged as promising platforms for remodeling the TNBC TME. These polymeric carriers can achieve tumor enrichment, enable controlled release, improve deep tissue penetration, and facilitate co-delivery of multiple therapeutic agents to exert synergistic effects. In this review, we adopt a barrier-to-design framework that directly links the major immunosuppressive barriers of the TNBC TME to corresponding polymer-engineering strategies. Unlike carrier-centered reviews that primarily catalog nanomaterial classes, we critically compare stimuli-responsive activation, sequential release, biomimetic targeting, local hydrogel depots, spatial targeting and multifunctional co-delivery according to their mechanistic rationale, preclinical evidence, model dependence, safety and translational feasibility. We further discuss subtype- and biomarker-informed patient selection, design requirements for primary tumors, tumor-draining lymph nodes and metastatic niches, and the need to balance multifunctionality against manufacturability. This framework provides a clinically oriented roadmap for developing barrier-matched PBDS as rational partners for TNBC immunotherapy.