Abstract

Immune checkpoint blockade has revolutionized cancer therapy by reactivating antitumor immunity, yet durable 
clinical responses remain limited to a subset of patients. Resistance arises from immune-suppressive tumor 
microenvironments, systemic toxicity, inadequate drug delivery, and adaptive immune escape mechanisms. 
Nano-immunoengineering has emerged as a powerful interdisciplinary strategy to address these limitations by 
integrating immunology, nanotechnology, and systems-level tumor biology. Programmable nanoparticles can 
be rationally designed to modulate immune checkpoints with high spatial, temporal, and cellular precision, 
enabling selective immune activation while minimizing off-target effects. These nanoplatforms facilitate 
targeted delivery of checkpoint inhibitors, gene regulators, peptides, and immunomodulatory agents, while also 
allowing co-delivery of synergistic therapeutics that reshape the tumor immune landscape. This review provides 
a comprehensive analysis of nano-immunoengineering approaches for remodeling immune checkpoints in 
cancer. We discuss immune checkpoint biology, nanoparticle design principles, targeting strategies, and 
mechanisms of immune reprogramming. Preclinical advances, combinatorial nano-immunotherapies, and 
translational challenges are critically evaluated. Collectively, programmable nanoparticles represent a 
transformative platform to overcome current barriers in cancer immunotherapy and advance precision immune 
checkpoint modulation.