Overcoming Immunosuppressive Niches in Solid Tumors: The Promise of Engineered Cell Membrane-Coated Nanoparticles

The tumor microenvironment (TME) of solid tumors is characterized by multiple, interconnected immunosuppressive niches—comprised of tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), abnormal vasculature, and a dense extracellular matrix (ECM)—that collectively blunt antitumor immunity and limit the efficacy of conventional and immune-based therapies. Cell membrane-coated nanoparticles (CMNPs), an emerging class of biomimetic nanoplatforms, combine the functional surface proteins and “self” markers of source cells with tunable synthetic cores to enable immune evasion, prolonged circulation, active targeting, and multi-modal cargo delivery. Recent engineering advances—such as hybrid and genetically modified membranes, ligand or antibody functionalization, and stimuli-responsive coatings—have expanded CMNP capabilities to actively remodel immunosuppressive niches by (i) delivering immune stimulants (e.g., STING agonists, TLR agonists), (ii) repolarizing TAMs, (iii) depleting or inhibiting MDSCs/Tregs, (iv) normalizing vasculature and ECM, and (v) enhancing antigen presentation and checkpoint blockade. This review critically examines the biological rationale, design strategies, mechanisms of action, recent preclinical advances, translational challenges, and future prospects for engineered CMNPs to overcome immunosuppressive niches in solid tumors. We highlight evidence supporting CMNP-mediated TME reprogramming, discuss limitations (manufacturing, characterization, safety, and regulatory hurdles), and outline research priorities that could accelerate clinical translation.