Engineering Nanoparticles to Modulate Extracellular Matrix and Immune Components of the Tumor Microenvironment in Cancer Immunotherapy.

Cancer immunotherapy has emerged as a transformative strategy for treating malignancies by harnessing the body's immune system. However, its clinical efficacy is often limited by the complex and immunosuppressive nature of the tumor microenvironment (TME), which poses substantial barriers to therapeutic success. The TME comprises a variety of components, including immune cells, cancer-associated fibroblasts, abnormal vasculature, extracellular matrix, and soluble mediators that collectively support tumor progression, suppress immune surveillance, and contribute to treatment resistance and poor prognosis. Recent advances in nanotechnology have introduced engineered nanomaterials as promising tools to modulate the TME and enhance the outcomes of cancer immunotherapy. These nanomaterials can be precisely engineered to interact with specific elements of the TME, enabling localized delivery, reduced systemic toxicity, and improved therapeutic efficacy. This review provides a comprehensive overview of the role of engineered nanoparticles in targeting both cellular and noncellular components of the TME. It highlights the capacity of nanocarriers to reprogram tumor-associated immune cells, including T cells, dendritic cells, natural killer cells, and tumor-associated macrophages, as well as their ability to target cancer-associated fibroblasts, remodel tumor vasculature, degrade the extracellular matrix, and modulate immunosuppressive mediators. By exploring these multifaceted interactions, we illuminate how rationally designed nanomaterials can reshape the tumor landscape to restore immune function and enhance immunotherapeutic efficacy. Finally, the review addresses current challenges, safety considerations, and future directions necessary to translate these innovations into clinically viable therapies.