STOML2: The Undercover Driver of Tumour Progression and Chemoresistance

Abstract

Chemoresistance remains a critical barrier to effective cancer therapy, significantly limiting clinical outcomes across diverse malignancies. Emerging evidence highlights the pivotal role of mitochondrial homeostasis governed by mitochondrial dynamics, biogenesis, and mitophagy in driving adaptive resistance mechanisms in cancer cells. Among the key regulators of these processes, Stomatin-like protein 2 (STOML2), a mitochondrial inner membrane protein, has gained increasing attention for its role in maintaining mitochondrial integrity and supporting tumor cell survival. Recent studies demonstrate that STOML2 modulates mitophagy through interactions with essential regulators such as PINK1 and PARL, thereby influencing the turnover of damaged mitochondria and promoting resistance to chemotherapeutic stress. In addition, STOML2 has been implicated in the activation of multiple pro-survival signaling pathways, including NF-κB, MAPK, and IL6/STAT3, further enhancing cancer cell proliferation, metabolic adaptability, and therapeutic evasion. Its involvement in mitochondrial biogenesis also enables cancer cells to meet elevated bioenergetic and biosynthetic demands, reinforcing its role in tumor progression. Notably, aberrant overexpression of STOML2 has been reported across various cancer types and is consistently associated with poor prognosis and reduced treatment responsiveness, underscoring its potential as both a prognostic biomarker and a therapeutic target. However, despite accumulating functional insights, the structural basis of STOML2 activity and its precise mechanistic contributions to mitochondrial quality control remain insufficiently characterized, limiting its translational exploitation. By integrating molecular, cellular, and translational perspectives, this work aims to provide a comprehensive framework for advancing STOML2-focused interventions in cancer therapy.