{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T05:03:38Z","timestamp":1779685418277,"version":"3.53.1"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T00:00:00Z","timestamp":1779667200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    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\u2013mesenchymal transition. In parallel, HHLA2 reshapes the tumor microenvironment through interleukin-10\u2013dependent macrophage M2 polarization, contributing to an immunosuppressive niche. Notably, the HHLA2\u2013KIR3DL3 axis directly suppresses CD8\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:sup>+<\/jats:sup>\n                    T cells. Targeting the HHLA2\u2013KIR3DL3 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.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1815639","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T04:36:06Z","timestamp":1779683766000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["HHLA2 as an emerging immune checkpoint in lung cancer: linking EGFR signaling, macrophage polarization, and CD8+ T-cell metabolic suppression"],"prefix":"10.3389","volume":"17","author":[{"given":"Juan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, General Hospital of Central Theater Command, PLA","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Army Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhong","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, General Hospital of Central Theater Command, PLA","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueting","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, General Hospital of Central Theater Command, PLA","place":["Wuhan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-025-01029-7","article-title":"Rechallenge with immune-checkpoint inhibitors in patients with advanced-stage lung cancer","volume":"22","author":"Tang","year":"2025","journal-title":"Nat Rev Clin 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