Loss of hepatocellular carcinoma-related protein 1 (HCRP1) (alias VPS37A) plays a role in endocytosis of receptor tyrosine kinases as a member of the ESCRT complex and has been linked to poor patient outcome in various types of epithelial cancer. To this date, the molecular and biological mechanisms explaining how its absence would contribute to tumor progression remain unknown. Using genomic editing with CRISPR-Cas9, we generated ovarian and breast cancer cell lines with loss-of-function mutations of HCRP1. We hypothesized that pathways downstream of receptor tyrosine kinases such as epidermal growth factor receptor are affected by HCRP1 loss and looked for deregulated signaling using immunoblotting and classical cancer biology assays. In our study, we show that endogenous deletion of HCRP1 leads to elevated phosphorylation of the transcription factor Signal transducer and activator of transcription 3 (STAT3) and induces upregulation of PD-L1, an important regulator of immune checkpoint inhibition. HCRP1 loss further leads to a mesenchymal phenotype switch in cancer cells, leading to increased proliferation and migration. Concludingly, our data emphasize the role of the tumor microenvironment in tumors with low or absent HCRP1 expression and suggest HCRP1 loss as a potential marker for metastatic potential and immunogenicity of epidermal growth factor receptor-driven cancer. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.