Exploring the potential role of PD-L2 in primary melanoma immunotherapy resistance: a hypothesis-driven dual-ligand framework
- 1Dalian Medical University, The First Affiliated Hospital, Department of Oncology
Abstract
Background: The treatment of melanoma has been significantly improved by immune checkpoint blockade (ICB); however, primary immune resistance, particularly in PD-L1-negative tumors and in selected treatment contexts, remains a critical efficacy bottleneck. Traditional biomarkers show clear limitations in explaining resistance mechanisms and guiding clinical stratification.
Objective: This review systematically proposes and elucidates the dual-ligand resistance model, comprehensively examines the molecular structure of programmed death-ligand 2 (PD-L2), its distinct dual-receptor interaction pattern with programmed death-1 (PD-1) and repulsive guidance molecule b (RGMb), and its multi-layered regulatory network, and explores the potential clinical value of PD-L2 as a context-dependent biomarker for primary immune resistance in melanoma and a potential therapeutic target.
Results: Within this framework, PD-L2 may contribute to immune escape in selected contexts, particularly in PD-L1-negative tumors or after PD-L1-targeted therapy. The expression of PD-L2 is regulated by genomic, epigenetic, microenvironmental, and host factors, with evidence of subtype-specific patterns. Available data suggest that PD-L2 may provide complementary biomarker value, although supporting evidence remains heterogeneous and prospective validation is limited. Targeting the PD-L2/RGMb axis has shown potential to reverse primary resistance in preclinical models, supporting further investigation.
Conclusion: This synthesis positions PD-L2 as a candidate compensatory checkpoint in primary immune resistance in melanoma within a proposed dual-ligand resistance framework. However, its role should be interpreted as context dependent rather than universal. Further melanoma-specific and clinically validated studies are needed to define its biomarker and therapeutic value.
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BibTeX
@article{song2026exploring,
title = {{Exploring the potential role of PD-L2 in primary melanoma immunotherapy resistance: a hypothesis-driven dual-ligand framework}},
author = {Wenjing Song and Yangyang Tao and Xiang Ji and Wanting Fu and Xin Cai and Xiu Shan},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1942224},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1942224/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Exploring the potential role of PD-L2 in primary melanoma immunotherapy resistance: a hypothesis-driven dual-ligand framework
AU - Wenjing Song
AU - Yangyang Tao
AU - Xiang Ji
AU - Wanting Fu
AU - Xin Cai
AU - Xiu Shan
PY - 2026
DA - 2026/10/19
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1942224
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1942224/full
AB - Background: The treatment of melanoma has been significantly improved by immune checkpoint blockade (ICB); however, primary immune resistance, particularly in PD-L1-negative tumors and in selected treatment contexts, remains a critical efficacy bottleneck. Traditional biomarkers show clear limitations in explaining resistance mechanisms and guiding clinical stratification. Objective: This review systematically proposes and elucidates the dual-ligand resistance model, comprehensively examines the molecular structure of programmed death-ligand 2 (PD-L2), its distinct dual-receptor interaction pattern with programmed death-1 (PD-1) and repulsive guidance molecule b (RGMb), and its multi-layered regulatory network, and explores the potential clinical value of PD-L2 as a context-dependent biomarker for primary immune resistance in melanoma and a potential therapeutic target. Results: Within this framework, PD-L2 may contribute to immune escape in selected contexts, particularly in PD-L1-negative tumors or after PD-L1-targeted therapy. The expression of PD-L2 is regulated by genomic, epigenetic, microenvironmental, and host factors, with evidence of subtype-specific patterns. Available data suggest that PD-L2 may provide complementary biomarker value, although supporting evidence remains heterogeneous and prospective validation is limited. Targeting the PD-L2/RGMb axis has shown potential to reverse primary resistance in preclinical models, supporting further investigation. Conclusion: This synthesis positions PD-L2 as a candidate compensatory checkpoint in primary immune resistance in melanoma within a proposed dual-ligand resistance framework. However, its role should be interpreted as context dependent rather than universal. Further melanoma-specific and clinically validated studies are needed to define its biomarker and therapeutic value.
SN - 1664-3224
ER -