SEMA3D (semaphorin 3D) is an axon guidance molecule that functions as a chemorepellent signal regulating neuronal growth cone collapse and neural migration. Beyond its classical neurobiological role, SEMA3D has emerged as a multifunctional protein with significant disease relevance in cancer and inner ear disorders. In pancreatic ductal adenocarcinoma (PDA), SEMA3D operates through dual tumor and nerve-derived sources. Tumor-derived SEMA3D binds to neuropilin receptors (particularly PLXND1) on dorsal root ganglion neurons, promoting perineural invasion and metastasis 1. Mechanistically, SEMA3D indirectly reprograms macrophages through KRASMUT-dependent ARF6 signaling in PDA cells, increasing lactate production that stimulates M2 macrophage polarization via GPCR132, thereby creating a pro-tumorigenic microenvironment 2. In contrast, SEMA3D shows tumor-suppressive functions in papillary thyroid carcinoma, where downregulation is associated with poor prognosis, and exogenous SEMA3D inhibits cancer cell proliferation and migration through MAPK/ERK pathway inhibition 3. Genetically, SEMA3D variants are implicated in familial Meniere's disease with variable expressivity and incomplete penetrance, linked to sensorineural hearing loss and vertigo 45. Additionally, SEMA3D represents a recurrent HPV integration hotspot in cervical carcinogenesis 6, suggesting context-dependent roles in cancer development.