A testable framework integrates platelet engineering and injectable hydrogels with CAR T cells for localized treatment of microscopic residual disease after breast cancer surgery

Abstract

Postoperative recurrence remains a major cause of treatment failure in breast cancer, largely because microscopic residual disease persists within a biologically active surgical niche characterized by inflammation, immune suppression, and spatially irregular tumor beds. In this review, we critically evaluate whether combining a precisely defined platelet-derived module, an injectable hydrogel, and CAR-T cells can provide nonredundant advantages over standard treatment and simpler local or pairwise alternatives in postoperative breast cancer. Platelet-inspired delivery systems exploit endogenous injury-homing and adhesion biology to improve localization to damaged vasculature and disease-relevant tissue, while hydrogels provide cavity-conformal retention, prolonged local release, and spatial control of therapeutic exposure within irregular surgical beds. CAR-T cells confer antigen-directed cytotoxicity to eliminate residual malignant cells that survive surgery and conventional adjuvant treatment. Importantly, the supporting evidence is tiered rather than uniform. Most studies have evaluated individual modules or selected pairwise combinations that directly support functions such as injury-associated localization, local retention, or antigen-directed cytotoxicity. Direct evidence of postoperative breast cancer is currently limited to intact platelet–B7-H3 CAR-T conjugates, a pairwise product that contains neither an injectable hydrogel nor a platelet-membrane-coated nanocarrier. The closest three-component precedent used a hyaluronic acid hydrogel to co-deliver CSPG4-directed CAR-T cells, IL-15-loaded polymer nanoparticles, and intact anti-PD-L1-conjugated platelets after resection of subcutaneous human melanoma in NSG mice. No published study has directly tested this defined platelet-membrane-coated nanocarrier–hydrogel–CAR-T product in postoperative breast cancer; therefore, interpret the construct discussed here as a hypothesis-driven, critical design perspective rather than a validated, disease-specific platform. We further discuss the potential of this integrated approach to improve control of microscopic disease within or immediately adjacent to the surgical bed and to remodel the local postoperative immune microenvironment. However, effects on regional nodal or distant relapse remain unproven and would require integration with regional radiotherapy and subtype-directed systemic therapy. Finally, we highlight the major barriers that must be resolved before clinical translation, including platelet-associated thrombogenicity, off-target biodistribution, CAR-T trafficking and persistence, antigen heterogeneity, manufacturability, and the need for predictive biomarker-guided patient selection. Collectively, this review reframes the postoperative breast cancer bed as a programmable therapeutic microenvironment and outlines a rational roadmap for next-generation adjuvant immunoengineering.