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Background  Early clinical trials indicate that patients with anaplastic lymphoma kinase (ALK)‐driven non‐small cell lung cancer (NSCLC) have a lower response rate to programmed cell death protein 1 (PD‐1) antibody therapy. However, the specific mechanism underlying this remains unclear. To further explore the characteristics of the tumor microenvironment and determine the potential mechanism of immunotherapy resistance in patients with ALK, we selected another important immune‐related molecule, major histocompatibility complex class I (HLA‐I), as the focus of our study.    Methods  We collected the biopsy samples of 140 patients with NSCLC. The number of CD8+ T cells and HLA‐I/programmed cell death 1 ligand 1 (PD‐L1) expression were determined by immunohistochemistry. Disease‐free survival (DFS) and overall survival (OS) were analyzed using the Kaplan–Meier method, and their relationship with patient clinical characteristics analyzed using Cox proportional hazards regression. In addition, we treated ALK‐positive lung cancer cells with ALK inhibitors in vitro to observe changes of HLA‐I.    Results  ALK positivity was associated with low membrane PD‐L1 and HLA‐I expression. However, these two indicators were not associated with the prognosis of patients with stage I–IIIa NSCLC. Inhibition of ALK could upregulate HLA‐I membrane expression to a certain extent.    Conclusion  Patients with ALK fusion showed downregulation of PD‐L1 and HLA‐I expression on the tumor cell membrane. Inhibition of ALK and its downstream signaling pathway can reverse it. These results suggest that the appropriate combination therapy should be considered for patients with ALK fusion and using targeted therapy at the proper time may increase patient benefits.

Downregulation of PD‐L1 and HLA‐I in non‐small cell lung cancer with ALK fusion