A Bispecific Peptide-Drug Conjugate Targeting LAG-3 and PD-L1 Harnesses Antitumor Immunity of Macrophages and T Cells.

Programmed cell death protein 1 (PD-1) and lymphocyte-activation gene 3 (LAG-3) are identified as key immune checkpoints on tumor-infiltrating macrophages, beyond their roles in T-cell functions. Blockade of LAG-3 and PD-1 pathways skews M2 macrophage polarization and shows antitumor efficacy independent of T cells. A bispecific peptide-drug conjugate, BsPep-IMDQ, was developed to simultaneously block both pathways and deliver a Toll-like receptor 7/8 (TLR7/8) agonist, imidazoquinoline (IMDQ), via a matrix metalloproteinase (MMP)-cleavable linker. This conjugate demonstrated potent tumor suppression in both anti-PD-1-responsive MC38 and -resistant B16 tumor models, promoting M1 macrophage polarization and CD8+ T-cell activation, while minimizing systemic toxicity. This work highlights macrophage targeting as a promising strategy for cancer immunotherapy.