**1. Introduction**

Emergence of immune checkpoint inhibitors was a turning point in the treatment of advanced nonsmall cell lung cancer (NSCLC). Therapies targeting the programmed cell death protein 1 (PD-1) checkpoint, such as nivolumab and pembrolizumab, have yielded impressive responsive rates in advanced NSCLC patients otherwise refractory to multiples lines of therapy [1–3]. However, the overall response rate for PD-1 inhibitor therapy is approximately 15–20% in unselected patients with NSCLC, and between 15% and 45% in patients with PD-L1-expressing NSCLC [4]. We need a biomarker that can more accurately predict the response to PD-1 inhibitors.

Expression of programmed death ligand-1 (PD-L1), the PD-1 ligand, is currently the most widely used biomarker for PD-1 inhibition. To identify patients who preferentially respond to PD-1 blockade, we need to better understand how the PD-1 pathway is regulated. Recently, several mechanisms have been reported to underlie PD-1 pathway regulation. CKLF-like MARVEL transmembrane-domain-containing 6 (CMTM6) regulates the PD-1 pathway by maintaining the expression of PD-L1, and CMTM6 is a predictor of the response to PD-1 inhibitors [5,6]. F-box only protein 38 (FBXO38) mediates PD-1 ubiquitination of T cells, and knockout of FBXO38 in such cells induces tumor progression in a mouse model due to increased PD-1 expression by tumor-infiltrating T cells [7]. AXL expression displays a positive correlation with PD-L1 expression in lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation, and abolition of AXL kinase activity inhibits *PD-L1* mRNA expression in a lung adenocarcinoma cell line with EGFR mutation [8].

Recent research has uncovered new strategies to remove specific unwanted proteins by using cellular protein degradation mechanisms, including lysosome-targeting molecules [9], proteolysis-targeting chimeras (PROTACs) [10], and tag-based degradation systems (dTAG) [11]. Wang et al. reported that Huntingtin-interacting protein 1-related protein (HIP1R) promotes lysosomal degradation of PD-L1, inhibits HIP1R-induced PD-L1 accumulation, and alters T cell–mediated cytotoxicity in a human colorectal cancer cell line [12]. A chimeric peptide including a lysosomal sorting signal and the HIP1R PD-L1-binding sequence significantly inhibits PD-L1 protein expression [12]. Although immune checkpoint inhibition is the most popular treatment for lung cancer, relationships involving HIP1R and immune checkpoint inhibitors in lung cancer have not been studied.

The present study was conducted to determine whether HIP1R protein expression affects the response of NSCLC patients to anti-PD-1 inhibitors and their prognosis. The relationship between HIP1R and PD-L1 was also evaluated, employing immunohistochemical and web-based mRNA expression data. In addition, we performed gene set enrichment analysis (GSEA) on RNA-sequencing data from The Cancer Genome Atlas (TCGA) to confirm the molecular pathways associated with HIP1R expression.
