Extracellular targeted protein degradation for tumor immune microenvironment reprogramming: from checkpoint blockade to checkpoint elimination

Immune checkpoint blockade has transformed oncology, yet many tumors remain refractory because suppressive proteins are replenished, recycled or distributed across poorly exposed tumor, myeloid and stromal compartments. Extracellular targeted protein degradation (eTPD) can route membrane or secreted proteins to endolysosomal destruction. We define checkpoint elimination as a degradation-mediated reduction in the total abundance of an established immune-checkpoint protein; the term does not imply complete or irreversible disappearance. This narrative review evaluates evidence at the level of target, target-bearing cell population, platform and model. Five dimensions are assessed: direct depletion, pathway dependency, target-matched function, in vivo activity and robustness or replication. Programmed death-ligand 1 (PD-L1) has integrated preclinical support across platforms, cell populations and checkpoint-responsive or -resistant models. Cluster of differentiation 47 (CD47) and cluster of differentiation 24 (CD24) connect target depletion to macrophage phagocytosis, although their strongest in vivo results are combination-supported. V-domain immunoglobulin suppressor of T-cell activation (VISTA) has direct degradation evidence with an incomplete functional and in vivo chain. Carbonic anhydrase IX (CAIX) depletion and macrophage migration inhibitory factor (MIF) uptake and intracellular processing extend investigation to broader suppressive tumor immune microenvironment (TIME) targets. Arginase 1-rich neutrophil extracellular traps and C-X-C motif chemokine ligand 12-rich stroma remain candidate target spaces without direct eTPD validation. The framework distinguishes protein degradation from surface internalization, masking, shedding, recycling and indirect downregulation, and separates preclinical target depletion from clinical benefit.