Exploring the potential role of PD-L2 in primary melanoma immunotherapy resistance: a hypothesis-driven dual-ligand framework

Abstract

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. 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. 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. 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.