Single nucleotide polymorphisms in PDCD1 (PD-1), CD274 (PD-L1), and PDCD1LG2 (PD-L2): current evidence and clinical significance in cancer immunotherapy.

Authors

Foteinos-Ioannis Dimitrakopoulos, Maria Loukopoulou, Anastasia Kottorou, Haralabos Kalofonos, Angelos Koutras

Published in

Cancer metastasis reviews. Volume 45. Issue 4. Nov 10, 2026. Epub Nov 10, 2026.

Abstract

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) have transformed cancer treatment, but durable benefit and immune-related adverse events (irAEs) remain difficult to predict. Germline single nucleotide polymorphisms (SNPs) in PDCD1, CD274, and PDCD1LG2 may influence checkpoint expression and immune-cell function. This narrative review integrates clinical association studies with available mechanistic evidence and evaluates effect estimates, endpoint definitions, replication, ancestry, and functional support. The leading candidates are PDCD1 rs7421861 for survival outcomes, PDCD1 rs10204525 for irAEs, CD274 rs822336 for response and survival, and CD274 rs822339 and rs1411262 for survival. However, most cohorts are small and retrospective, allele coding is not always harmonized, and genotype-by-treatment interaction analyses are uncommon. No variant has therefore been validated for routine clinical use. Future studies should use prespecified endpoints and genetic models, adjusted estimates with 95% confidence intervals, appropriate multiple-testing correction, standardized allele and genome-build reporting, and independent multi-ancestry validation. Prospective biomarker-stratified trials should determine whether these variants improve prediction beyond PD-L1 immunohistochemistry, tumor mutational burden, microsatellite instability or mismatch-repair status, and established clinical factors. Multicenter consortia and individual participant data meta-analyses will be required to establish whether these germline markers can contribute to treatment selection or toxicity monitoring.

PMID:
43007529
Bibliographic data and abstract were imported from PubMed on 11 Nov 2026.

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