The STEAP Protein Family: Transmembrane “Express Channels” and the Next Promising Targets in Cancer Therapy

In 2025, research on the STEAP protein family achieved pivotal breakthroughs in both mechanistic understanding and clinical translation. Structural biology studies directly demonstrated for the first time that the intracellular domain of STEAP2 binds reduced NADPH, elucidating the core mechanism of its electron transfer activity. At the same time, STEAP1 was shown to function through forming a complex with cytochrome b5 reductase. In prostate cancer, STEAP1 and STEAP2 can assemble into homo- or hetero-trimeric complexes, a property that significantly influences the efficacy of targeted therapeutic agents.

The STEAP family comprises a group of mammal-specific six-transmembrane proteins, including four core members: STEAP1, STEAP2, STEAP3, and STEAP4. Structurally, they share a defining feature—each contains six transmembrane helices, with both the N- and C-termini located in the cytoplasm. This unique membrane topology enables STEAP proteins to span the cell membrane and carry out functions in substrate transport and electron transfer.

Although the STEAP family name contains the term “prostate,” its members exhibit broad, tissue-specific expression patterns that are not restricted to prostate tissue. STEAP1 is highly expressed in prostate cancer (with low expression in normal prostate) and is also detected in bladder and breast cancers. STEAP2 is predominantly expressed in the prostate and is overexpressed in prostate cancer. STEAP3 shows high expression in hematopoietic tissues and the liver, but its expression is reduced in prostate cancer. STEAP4 is highly expressed in adipose tissue and the liver and is broadly distributed across multiple tumor types.

This tissue-specific expression landscape makes STEAP family members important targets for cancer therapy. In particular, the high expression of STEAP1 and STEAP2 in prostate cancer has positioned them as leading targets for prostate cancer–directed therapies, while STEAP3 and STEAP4 demonstrate therapeutic potential in other tumor types. At present, the development of STEAP-targeted therapeutics has made significant progress, including Amgen’s STEAP1/CD3 bispecific antibody AMG 509, which has entered phase III clinical trials, and AstraZeneca’s STEAP2 antibody–drug conjugate AZD0516, which has initiated phase I/II clinical studies—opening new avenues for cancer treatment.

The core function of STEAP proteins is to act as metal reductases, catalyzing the reduction of ferric iron (Fe³⁺) and cupric copper (Cu²⁺). This process is essential for maintaining intracellular metal ion homeostasis and directly influences cellular energy metabolism and redox balance. From an evolutionary perspective, STEAP proteins belong to the ferric reductase superfamily and share structural and functional similarities with NADPH oxidases.

Distinct STEAP family members have diverged functionally: STEAP3 plays a critical role in physiological iron uptake and turnover, whereas STEAP4 is more closely involved in responses to nutritional and inflammatory stress, as well as in fatty acid and glucose metabolism.

Drug development efforts targeting the STEAP family have been primarily focused on STEAP1, leveraging multiple therapeutic platforms. These include bispecific antibodies, antibody–drug conjugates (ADCs), CAR-T cell therapies, and small-molecule inhibitors, in which STEAP1-directed programs are among the most advanced. As our understanding of the biological functions of the STEAP family continues to deepen, the importance of these proteins in cancer diagnosis and therapy is becoming increasingly evident.

Evolving from metal reductases to cancer biomarkers and ultimately to therapeutic targets, the diverse functions of the STEAP family open new possibilities for precision oncology. Current drug candidates under development targeting STEAP family members include:

Table 1. Functional Characteristics of STEAP Family Members and Their Associations with Cancer

To accelerate the development of STEAP family–targeted therapeutics in cancer treatment, Kyinno Biotechnology has established engineered cell lines with overexpression of STEAP1, STEAP2, STEAP3, and STEAP4, as well as knockout cell lines for STEAP1, STEAP2, and STEAP3. These models support the entire drug discovery and development pipeline—from early target validation and compound screening to pharmacology/efficacy evaluation and late-stage resistance mechanism studies—thereby substantially reducing the risk of failure in subsequent clinical trials and facilitating the translation of safe and effective STEAP-targeted therapies into the clinic.

In addition to custom cell line engineering, Kyinno Biotechnology also offers integrated services including antibody discovery, antibody expression, off-target screening, and in vitro and in vivo pharmacological evaluation. We welcome you to contact us for more information.

Products and Services List: