Antibody-nanoparticle conjugates for precision targeting of immunosuppressive tumor microenvironment

Cancer continues to be a significant global health and socioeconomic issue, with an unequal mortality rate in low- and middle-income nations. The progression of tumors is influenced by both intrinsic changes within cancer cells and the tumor microenvironment (TME), which is a dynamic collection of stromal cells, immune infiltrates, extracellular matrix, and soluble mediators that together encourage immune suppression, angiogenesis, and resistance to treatment. Antibody-conjugated nanoparticles (ACNPs) combine antibody-mediated molecular recognition with nanoscale drug delivery systems to selectively target malignant cells and important components of the TME. In preclinical and early clinical studies, representative ACNP classes, including monoclonal antibodies or antibody fragments conjugated to liposomes, polymeric nanoparticles, metallic cores, or lipid-polymer hybrids, have exhibited enhanced tumor association and context-dependent intratumoral delivery, as well as the ability to modulate suppressive TME elements such as M2-like tumor-associated macrophages and cancer-associated fibroblasts. Nonetheless, clinical translation is impeded by significant biological and translational obstacles, such as tumor heterogeneity, restricted tissue penetration, swift elimination by the mononuclear phagocyte system, immunogenicity-associated safety concerns, and challenges in manufacturing and scaling up. In this paper, we critically examine ACNP design strategies, compare antibody formats and conjugation chemistries, and compile mechanistic evidence from in vitro, in vivo, and early clinical studies published up to 2025. We further investigate ACNP-based combination regimens targeting TME modulation and conclude by delineating translational priorities and practical design considerations necessary for achieving consistent therapeutic efficacy in heterogeneous human tumors.