ReviewFrontiers in immunology2026
HHLA2 as an emerging immune checkpoint in lung cancer: linking EGFR signaling, macrophage polarization, and CD8
Review in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Immune checkpoint blockade has revolutionized the treatment of lung cancer; however, therapeutic responses remain heterogeneous, particularly in patients harboring activating epidermal growth factor receptor (EGFR) mutations. Emerging evidence identifies human endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2), a novel B7 family member, as a genotype-associated immune checkpoint enriched in EGFR-mutant lung cancer. Beyond its classical role in T-cell inhibition, HHLA2 appears to integrate tumor-intrinsic oncogenic signaling with immune microenvironment remodeling. Recent studies demonstrate that HHLA2 promotes tumor progression by enhancing EGFR/MAPK/ERK signaling, thereby supporting proliferation, invasion, and epithelial-mesenchymal transition. In parallel, HHLA2 reshapes the tumor microenvironment through interleukin-10-dependent macrophage M2 polarization, contributing to an immunosuppressive niche. Notably, the HHLA2-KIR3DL3 axis directly suppresses CD8
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