HHLA2 as an emerging immune checkpoint in lung cancer: linking EGFR signaling, macrophage polarization, and CD8+ T-cell metabolic suppression.

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+ T-cell glutamine metabolism, introducing a metabolic checkpoint mechanism that limits cytotoxic function and facilitates immune evasion. Clinically, lower HHLA2 expression has been associated with improved response to neoadjuvant immunotherapy and increased tissue-resident memory T-cell infiltration, suggesting predictive biomarker potential. Collectively, HHLA2 represents a multifunctional immune checkpoint that links oncogenic EGFR signaling, macrophage polarization, and metabolic suppression of CD8+ T cells. Targeting the HHLA2-KIR3DL3 axis, particularly in combination with EGFR tyrosine kinase inhibitors, may provide a rational precision immunotherapy strategy for EGFR-mutant lung cancer. Further mechanistic and translational studies are warranted to fully define its therapeutic value.