Abstract: The Plexin-B family, comprising Plexin-B1, Plexin-B2, and Plexin-B3, represents a class of single-pass transmembrane receptors whose context-dependent functional outputs are governed by six contextual determinants-ligand availability, co-receptor expression, downstream signaling state, cell type, microenvironmental cues, and disease stage—exhibiting striking functional duality in cancer progression. This review provides a comprehensive overview of the bidirectional regulatory mechanisms of Plexin-B receptors across multiple malignancies. This functional duality is exemplified by Plexin-B1, which promotes glioma invasion via RhoA/PI3K/AKT signaling yet suppresses early-stage melanoma progression through FAK/Rho inhibition; similarly, Plexin-B2 drives triple-negative breast cancer stemness while restricting skin cancer growth via YAP suppression. A central thesis of this review is that these six contextual determinants establish a framework for understanding receptor pleiotropy. Furthermore, while targeting Plexin-B signaling shows therapeutic promise (eg, pepinemab in clinical trials), indiscriminate inhibition risks abrogating tumor-suppressive functions and perturbing immune microenvironment homeostasis, underscoring the necessity for biomarker-driven stratification to prevent paradoxical oncogenic consequences. Keywords: plexin-B family, semaphorin, c-Met, dual regulatory function, tumor microenvironment, Rho GTPase signaling
Mao et al. (Wed,) studied this question.