CD160-HVEM axis signaling drives T-cell exhaustion in cancer and promotes allograft rejectionNew Research Explores Tifcemalimab for Cancer and Autoimmune Diseases

The clinical success of immune checkpoint blockade (ICB) in oncology has validated the existence of molecular brakes that restrain T-cell immunity. While releasing these brakes unleashes antitumour responses, their physiological role is to maintain self-tolerance. This review explores the reciprocal paradigm of the CD160–HVEM axis across three disease settings: immuno-oncology, autoimmunity and transplantation. CD160–HVEM signalling can enforce pathological T-cell exhaustion in cancer, yet its failure or costimulatory co-option can precipitate autoimmunity or accelerate allograft rejection. Unlike programmed cell death protein 1 (PD-1), CD160 operates within a bidirectional network involving herpesvirus entry mediator (HVEM; TNFRSF14), B- and T-lymphocyte attenuator (BTLA) and LIGHT (TNFSF14). The axis is expressed across lymphocytes, myeloid cells, epithelium, endothelium and malignant B cells. Mouse and human biology of the axis are not interchangeable: murine CD160 is a broad major histocompatibility complex (MHC) class I and CD1d receptor, whereas human natural killer (NK) triggering is dominated by HLA-C, and the transmembrane isoform CD160-TM is human-characterised. Structural diversity, from an inhibitory glycosylphosphatidylinositol (GPI)-anchored form to activating CD160-TM on NK cells, positions CD160 as a tunable rheostat rather than a linear checkpoint. While direct anti-CD160 candidates remain in advanced preclinical development, other components of the HVEM network are undergoing human clinical testing. The most mature clinical programme is tifcemalimab, an anti-BTLA monoclonal antibody, not an anti-CD160 agent. Antagonistic anti-HVEM antibodies (Demerlé anti-HVEM18–10 in humanised mice; preclinical fully human 4CB1, mechanistically related but distinct) block HVEM engagement by both BTLA and CD160. Because CD160 is inhibitory on T cells but activating on NK cells via CD160-TM, a systemic antibody to the shared ectodomain is a dual-function drug-design constraint, not a simple checkpoint blockade. Precision use of this axis requires isoform, cell type, interaction geometry and disease context to be specified before a direction of intervention is chosen. Next steps are biomarker-qualified enrichment, isoform-discriminating reagents, and correlative CD160 profiling inside ongoing BTLA–HVEM studies. Pathological exhaustion that shields tumours remains a map for restoring tolerance in autoimmunity and for blocking CD28-independent rejection in transplantation.