Extracellular targeted protein degradation for tumor immune microenvironment reprogramming: from checkpoint blockade to checkpoint elimination
4 affiliations
- 1Longhua Hospital, Shanghai University of Traditional Chinese Medicine
- 2Dongzhimen Hospital, Beijing University of Chinese Medicine
- 3Beijing Anzhen Hospital, Capital Medical University
- 4Guang’anmen Hospital, China Academy of Chinese Medical Sciences
Abstract
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.
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BibTeX
@article{gu2026extracellular,
title = {{Extracellular targeted protein degradation for tumor immune microenvironment reprogramming: from checkpoint blockade to checkpoint elimination}},
author = {Yuanye Gu and Zheyu Xu and Jiayao Zhao and Haobo Li and Tian Xia and Qingyuan Chi and Shuangshuang Ma and Ruonan Qiang and Xian Gu},
journal = {Frontiers in Oncology},
year = {2026},
month = oct,
doi = {10.3389/fonc.2026.1954751},
url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1954751/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Extracellular targeted protein degradation for tumor immune microenvironment reprogramming: from checkpoint blockade to checkpoint elimination
AU - Yuanye Gu
AU - Zheyu Xu
AU - Jiayao Zhao
AU - Haobo Li
AU - Tian Xia
AU - Qingyuan Chi
AU - Shuangshuang Ma
AU - Ruonan Qiang
AU - Xian Gu
PY - 2026
DA - 2026/10/21
JO - Frontiers in Oncology
DO - 10.3389/fonc.2026.1954751
UR - https://www.frontiersin.org/articles/10.3389/fonc.2026.1954751/full
AB - 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.
SN - 2234-943X
ER -