Neoadjuvant immunochemotherapy (nICT) has reshaped the treatment paradigm for locally advanced esophageal cancer (EC), but patient responses remain highly heterogeneous. Reliable biomarkers to predict therapeutic benefit are urgently needed. Class I human leukocyte antigen (HLA-I) molecules are essential for anti-tumor immunity, presenting neoantigens to cytotoxic T lymphocytes.This study investigated the relationship between germline HLA-I genotypes and treatment response in patients with esophageal cancer receiving nICT.

We retrospectively analyzed 30 Chinese EC patients who underwent surgery following nICT. High-resolution sequencing was used to determine germline HLA-I genotypes. Associations between specific HLA alleles and both short-term pathologic response and long-term survival outcomes, including pathologic complete response (pCR) and event-free survival (EFS) were evaluated.

HLA-A*11:01 carriers exhibited significantly prolonged EFS compared with non-carriers (P = 0.015). In contrast, the HLA-A*24:02 allele was more frequent in non-pCR patients (50.0% vs. 12.5%, P = 0.064), and shorter EFS was observed among carriers (median 16.0 vs. 38.8 months, P = 0.063), although these differences did not reach statistical significance. HLA-I homozygosity was more common among patients who achieved pCR (75.0% vs. 27.3%, P = 0.034).

In this small retrospective cohort, germline HLA-I genotypes were associated with differences in pathologic response and event-free survival following nICT. These findings should be interpreted as exploratory and hypothesis-generating, requiring validation in larger prospective studies before clinical translation.