Advances in nanodelivery systems based on tumor-associated cell reprogramming strategies for enhanced tumor therapy

Tumor-associated cells primarily comprise immune cells and stromal cells, which collectively construct tumor microenvironment (TME) through complex interactions. This environment not only accelerates tumor immune escape but also leads to chemotherapy resistance and immunotherapy failure, significantly increasing the risk of tumor progression and metastasis. Fortunately, these cells often exhibit phenotypic heterogeneity, allowing reprogramming strategies to transform their anti-tumor phenotypes into pro-tumor ones, thereby exerting beneficial regulatory effects on tumor progression. Nanodelivery systems (NDSs) offer significant advantages such as precise targeting and efficient delivery, making them crucial for implementing reprogramming strategies. Consequently, utilizing NDSs to reprogram tumor-associated cells for enhanced tumor therapy presents a promising solution. This review innovatively summarizes the fundamental roles, functional phenotypes, and diverse reprogramming strategies for immune cells and stromal cells within the TME. It then details therapeutic approaches by targeting distinct tumor-associated immune cells and stromal cells. Furthermore, it discusses the opportunities and challenges NDSs-based on reprogramming strategies to achieve cellular phenotype conversion. This review aims to advance our understanding of reprogramming tumor-associated immune or stromal cell phenotypes to enhance tumor therapy. STATEMENT OF SIGNIFICANCE: The tumor microenvironment (TME), largely orchestrated by heterogeneous populations of immune and stromal cells, is a pivotal determinant of therapeutic resistance and disease progression. Reprogramming these tumor-associated cells from pro-tumorigenic to anti-tumorigenic phenotypes represents a transformative strategy to overcome immune evasion, chemotherapy resistance, and immunotherapy failure. This review underscores the critical innovation of leveraging nanodelivery systems (NDSs) to precisely and efficiently implement such reprogramming strategies. By systematically synthesizing the roles, phenotypic states, and reprogramming approaches for key cellular components within the TME, this work provides a comprehensive framework for advancing targeted nanomedicine. It not only elucidates current therapeutic paradigms but also critically examines the prospects and challenges of integrating NDSs to achieve phenotypic conversion, thereby offering essential insights for the development of next-generation, microenvironment-focused cancer therapies.