Anti-PD-1 single-chain variable fragments (scFVs) offer modular, localized cancer immunotherapy with potential for improved cost-effectiveness.

Cancer immunotherapy targeting the programmed death-1 (PD-1) immune checkpoint has revolutionized oncology by reversing T-cell exhaustion and immune evasion. However, current PD-1/PD-L1 monoclonal antibodies (mAbs) face significant hurdles, including their large size, propensity for systemic toxicities, and high production costs, limiting broader application. This creates a critical need for more targeted and cost-effective alternatives. Anti-PD-1 single-chain variable fragments (scFVs) are being developed to address these gaps, offering the potential for localized immune modulation within the tumor microenvironment.

This review article synthesizes the therapeutic development, functional applications, and translational advances of anti-PD-1 single-chain variable fragments (scFVs) in cancer immunotherapy. It details how advances in phage-display libraries and antibody engineering have enabled high-affinity scFVs. The authors discuss diverse applications: bispecific/trispecific constructs, antibody-drug conjugates (ADCs), immunotoxins, nanoparticles, and biological vector carriers. The review also covers engineered immune cells (CAR-Ts, NK cells, MSCs) secreting or displaying scFVs, and oncolytic/non-replicating viral vectors for tumor-confined activity.