BACKGROUND: Perineural invasion (PNI) is a prevalent phenomenon in salivary adenoid cystic carcinoma (SACC). Nevertheless, the regulatory mechanism of PNI is largely elusive. METHODS: We detected Apolipoprotein D (ApoD) expression and further determined its role in SACC progression. Subsequently, the contributions of SACC-derived ApoD on neurite outgrowth of dorsal root ganglions (DRGs) cells were explored. Moreover, a series of in vivo assays were conducted to elucidate the role of ApoD in the SACC PNI process. RESULTS: We observed a dramatic up-regulation of ApoD in the SACC associated with an enhancement of PNI in patient biopsies. We found that SACC-derived ApoD elevated cancer cell migration and invasion. In addition, ApoD could facilitate the neurite outgrowth of cultured DRG cells in a CXCR4-dependent manner in vitro, as well as innervation, angiogenesis, and invasion along peripheral nerves of SACC in vivo. More importantly, by advanced bioinformatic analysis, we unexpectedly revealed a novel phenomenon 'tumour cell to neuron-like cell transition' in the ApoD-rich microenvironment in vivo, contributing to the neurogenesis in the SACC tumour. CONCLUSION: we discovered a novel role of cancer-derived ApoD in the pathogenesis of PNI, which may represent an effective therapeutic target for SACC in clinics.