Roles and clinical translational prospects of TMEM proteins in the tumor immune microenvironment.

Transmembrane proteins have emerged as pivotal regulators of the tumor immune microenvironment. They coordinate immune regulation through the modulation of antigen presentation, cytokine signaling, ion homeostasis, and immune checkpoint activity. A growing body of evidence highlights their dual functional roles: certain TMEM family members promote antitumor immunity by enhancing immune activation, while others contribute to immune evasion in a context-dependent manner influenced by cellular and tissue environments. Notably, TMEM173 (STING) and TMEM176B exemplify the immune-activating and context-dependent regulatory functions of this family, underscoring its therapeutic potential. Despite these advances, the majority of TMEM proteins remain incompletely characterized, with limited insights into their molecular architectures, interaction networks, and context-specific regulatory mechanisms. Furthermore, challenges related to selective targeting and the safe translation of findings into clinical applications continue to impede therapeutic development. This review summarizes recent progress in understanding TMEM-mediated mechanisms within the tumor immune microenvironment, underscores their potential as therapeutic targets and prognostic biomarkers, and discusses key challenges and future directions for integrating TMEM biology into precision immunotherapy.