PD-1 x CTLA-4

Class

PD-1/CTLA-4 bispecific antibody (volrustomig)

Pathway

co-blocks the PD-1 and CTLA-4 immune checkpoints on a single molecule to enhance T-cell anti-tumor activity, with preferential CTLA-4 blockade on PD-1-co-expressing (tumor-reactive) T cells

PD-1 and CTLA-4 are two distinct inhibitory receptors, or checkpoints, expressed on T cells that normally prevent excessive or self-directed immune responses. Tumors exploit both pathways to escape immune attack: CTLA-4 dampens T-cell activation early, during priming in lymph nodes, by outcompeting a costimulatory receptor for shared ligands on antigen-presenting cells, while PD-1 suppresses already-activated T cells within tissues, including tumors, when it engages its ligand PD-L1. Blocking either checkpoint alone can restore anti-tumor T-cell function, but resistance and incomplete responses are common, prompting interest in blocking both simultaneously. A bispecific antibody that engages PD-1 and CTLA-4 on the same molecule is designed to concentrate CTLA-4 blockade on T cells that also express PD-1 (a population enriched for tumor-reactive, chronically stimulated cells) rather than blocking CTLA-4 broadly across the T-cell repertoire. This selectivity is intended to preserve efficacy while limiting the diffuse T-cell activation that drives toxicity when CTLA-4 is blocked systemically. This mechanism is broadly relevant across solid tumors where checkpoint-mediated immune evasion contributes to disease progression, and reflects a general strategy of combining complementary checkpoint blockade within a single engineered molecule rather than as separate, independently dosed antibodies.