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.