The human six-transmembrane epithelial antigen of the prostate (STEAP) proteins, which include STEAP1–4 and atypical STEAP1B, contain six transmembrane domains and are located in the cell membrane. STEAPs are considered archaeal metal oxidoreductases, based on their heme groups and F420H2:NADP+ oxidoreductase (FNO)-like structures, and play an important role in cell metal metabolism. Interestingly, STEAPs not only participate in biological processes, such as molecular transport, cell cycling, immune response, and intracellular and extracellular activities, but also are closely related to the occurrence and development of several diseases, especially malignant tumors. Up to now, the expression patterns of STEAPs have been found to be diverse in different types of tumors, with controversial participation in different aspects of malignancy, such as cell proliferation, migration, invasion, apoptosis, and therapeutic resistance. It is clinically important to explore the potential roles of STEAPs as new immunotherapeutic targets for the treatment of different malignant tumors. Therefore, this review focuses on the molecular mechanism and function of STEAPs in the occurrence and development of different cancers in order to understand the role of STEAPs in cancer and provide a new theoretical basis for the treatment of diverse cancers.

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BACKGROUND Immune cells play a role in the regulation of tumor cell behavior, and accumulating evidence supports their significance in predicting outcomes and therapeutic efficacy in colorectal cancers (CRC). Human six-transmembrane epithelial antigen of the prostate (STEAP) proteins have been recognized and utilized as promising targets for cell- and antibody-based immunotherapy. One STEAP family member, STEAP4, is expected to be an attractive biomarker for the immunotherapy of prostate and breast cancer. However, the immunotherapeutic role of STEAP4 for colorectal carcinomas has not been demonstrated. AIM To explore the expression pattern of STEAPs in CRC and their relationship with immune infiltration, and investigate the potential utilization of STEAPs as novel prognostic indicators in colorectal carcinomas. METHODS The expression level of STEAPs in CRC was evaluated using various open-resource databases and online tools to explore the expression characteristics and prognostic significance of STEAPs, as well as their correlation with immune-related biomarkers, such as immune infiltration. Immunohistochemical (IHC) experiments were subsequently performed to verify the database conclusions. RESULTS The levels of STEAPs in CRC were inconsistent. The expression of STEAPs 1-3 in CRC was not significantly different from that in normal tissues. However, STEAP4 mRNA levels were significantly lower in CRC than in normal tissue and were positively correlated with immune-related biomarkers, such as immune cell infiltration, immune stimulation, major histocompatibility complex levels, and chemokines. Interestingly, the expression of STEAP4 in microsatellite instability-high CRC subtype was higher than that in microsatellite stability subtype. IHC staining was performed on colon cancer tissue samples and showed that high expression of STEAP4 in adjacent tissues positively correlated with immune-related biomarkers, including MLH1, MLH6, and PMS2, but negatively correlated with programmed death ligand 1, to varying degrees. CONCLUSION Our results provide an analysis of the expression of STEAP family members in CRC. Among different STEAP family members, STEAP4 plays a different role in CRC compared to STEAPs 1-3. In CRC, STEAP4 expression is not only lower than that in normal tissues, but it is also positively correlated with immune infiltration and immune-related biomarkers. These findings suggest that STEAP4 may be a potential biomarker for predicting CRC immune infiltration status.