Targeting PD-L2–galectin-9 interactions restores immunity in cancer and infectious diseases

Immunity against cancer and infection is often disrupted by immunosuppressive pathways, yet mechanisms that promote immune-activation remain poorly defined. Using biochemical, spatial‑omics, high‑resolution imaging and mechanistic approaches, we identified a previously unrecognized interaction between PD‑L2 and Galectin‑9 (GAL9). This interaction promotes the assembly of GAL9 lattices on activated immune cells, which cluster receptors to amplify immune activation, whereas their disruption contributes to immune failure in cancer and infection. Restoring lattice formation with multimeric-PD‑L2 or a novel anti‑GAL9 antibody re‑established immune function. Anti‑GAL9 therapy cured lethal malaria and eliminated palpable colon and breast tumors in preclinical models by enhancing functions of multiple immune cell types and their spatial organization while inducing durable, vaccine‑like memory protection. Anti‑GAL9 reinvigorated immune function in microsatellite‑stable colorectal cancer patient cells, a setting non‑responsive to current immunotherapies. These findings define the PD-L2–GAL9 axis as a major immune-activation pathway and therapeutic strategy for cancer and infectious disease