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Immunotherapy utilizing natural killer cell-activated receptor natural-killer group-2 member D ligands (NKG2DLs) has had preclinical success in the treatment of small cell lung cancer. The present study aimed to investigate the association between NKG2Ls and chemoresistance. The mRNA expression of six NKG2DLs associated with progression-free survival time (PFS) and first-line chemotherapy were assessed in the present study. Major histocompatibility complex class I polypeptide-related sequence A (MICA)-overexpressing NCI-H446 cell line was constructed, and the mRNA expression levels of 11 genes associated with chemotherapy sensitivity were determined. The results demonstrated that MICA was positively and significantly associated with PFS. Furthermore, MICA expression was 1.6 times higher in patients with prolonged PFS compared with the rapid chemoresistance group. ATP binding cassette subfamily G member 2 (ABCG2) mRNA expression was associated with chemotherapy resistance and significantly downregulated in the cell line overexpressing MICA. Moreover, following addition of nicardipine (an ABCG2 inhibitor), chemotherapeutic sensitivity increased in the MICA-overexpressing cell line. Taken together, the results of the present study suggested that MICA may enhance the chemosensitivity of patients with extensive small cell lung cancer by downregulating ABCG2. [ABSTRACT FROM AUTHOR]