support the current understanding that oral cancer pain is attributed to release of mediators from the cancer and micro environment. On the one hand, the media tors sensitize or activate primary afferent sensory neurons that respond to nociceptive stimuli (nociceptors) and induce sprouting of sensory and sympathetic neurons into the microenvironment. [7][8][9][10] On the other hand, neuropeptides released from sensory neurons promote cancer. [10,11] Neuropeptides induce epidermal proliferation, angiogen esis, perineural invasion, and transforma tion of stromal cells. [12][13][14][15][16] The mechanisms of reciprocal interaction between oral cancer cells and neurons, and how the interactions promote cancer and pain, are not known. There is a need to define the mechanisms by which oral cancers and neurons interact with each other and the efficacy of dis rupting this interaction to treat oral cancer and associated pain. Patients with regional/nodal metastasis (N+) oral cancer experience greater pain than patients without metastasis (N0). [5,17] Patient reported pain on the University of California San Francisco Oral Cancer Pain Questionnaire [5] has potential to identify the presence of metas tasis prior to surgery to remove the cancer. [17] Proteins encoded by genes differentially expressed in N+ cancers from patients with high levels of pain, "pain and metastasis genes," are enriched for functions in extracellular matrix organization and angiogenesis. These genes have oncogenic and neuronal func tions. This set of genes overlaps with the metasignature of the partial epithelialtomesenchymal transition (pEMT) program, also recently described as an independent predictor of lymph node metastasis in HNSCC. [18,19] Pain and metastasis genes have been identified as cargo of extracellular vesicles (EVs) in publicly available databases such as ExoCarta. [20] Depletion of EVs from cancer cell line conditioned media (CM) reversed CMinduced thermal and mechanical allodynia in a mouse model, implicating EVs in the transport of pain mediators. [17] Extracellular vesicles carry proteins, nucleic acids, and lipids and provide a means of communication between cells. [21] Cancers release elevated levels of EVs and the protein cargo of EVs is cancer type specific. [21,22] EVs released into the circulation and their cargo are potential biomarkers for cancer detection and diagnosis of cancer type. [22] Recent studies highlight EV heterogeneity. [23][24][25] Subpopulations of EVs and nano particles, collectively referred to as EVPs, differ in size and cargoes. Small EVs (sEVs) or exosomes (40-150 nm in diameter) are formed within the endosomal system as intralumenal vesicles of multi vesicular bodies (MVBs) and are released into the extracellular Oral cancer pain is attributed to the release from cancers of mediators that sensitize and activate sensory neurons. Intraplantar injection of conditioned media (CM) from human tongue cancer cell line HSC-3 or OSC-20 evokes nociceptive behavior. By contrast, CM from noncancer cell lines, DOK, ...