Programmed cell death protein 1–Cytotoxic T-lymphocyte-associated protein 4 cell-surface interface (PD-1–CTLA-4 interface)

The PD-1–CTLA-4 cell-surface interface refers to the direct physical interaction, or cis-interaction, between Programmed cell death protein 1 (PD-1) and Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) on the surface of the same T cell (Akkaya et al., Nature 2024). This interaction is a key regulatory mechanism that modulates the inhibitory signaling of these two major immune checkpoints, which are essential for maintaining immune homeostasis and preventing autoimmunity (Pardoll, Nature Reviews Cancer, 2012). In the tumor microenvironment, the co-expression and interaction of these receptors on tumor-infiltrating lymphocytes contribute to T-cell exhaustion and immune evasion by the cancer. The interface has become a significant therapeutic target for bispecific antibodies, such as volrustomig and cadonilimab, which are designed to bind both receptors simultaneously (Dummer et al., Nature Reviews Clinical Oncology, 2022). These drugs aim to disrupt the inhibitory complex more effectively than combination monotherapies, thereby enhancing the anti-tumor immune response. By targeting the interface, these therapies seek to reinvigorate exhausted T cells and improve clinical outcomes in patients with various malignancies (ClinicalTrials.gov, 2024).

Other names

PD-1:CTLA-4 cis-complexPD-1/CTLA-4 heterodimerPD-1–CTLA-4 cis-interactionPD-1:CTLA-4 interface

Dual blockade of PD-1 and CTLA-4 inhibitory pathways, potentially disrupting the cis-inhibitory complex to enhance T-cell receptor (TCR) signaling and T-cell proliferation (Akkaya et al., Nature 2024; Pardoll, Nature Reviews Cancer, 2012).