Oral cavity-related cancers account for 53,000 cases and 10,860 deaths in the United States annually. The most common type is oral squamous cell carcinoma (OSCC). We have identified an epigenetic regulator, Lysine-specific demethylase 1 (LSD1), upregulated in dysplasia and progression to malignant phenotype leading to OSCC. We showed that LSD1 attenuation inhibits patient-derived xenograft, EGFR and YAP signaling critical in OSCC. Recent preliminary studies showed that conditional LSD1 deletion in the tongue epithelium during dysplasia reduced invasive pathological lesions, downregulated EGFR, YAP-induced signaling network, and Pd- L1 expression. Interestingly, LSD1 inhibition attenuates IL-6-JAK-STAT3 novel signaling identified in two independent studies: 1) proteomics analysis of Lsd knockout mice preneoplasia and 2) single-cell RNAseq analysis using LSD1 inhibitor. Of note, IL-6-JAK-STAT3 is a specific target in breast and other cancer stem cells and immune cells. This indicates that LSD1 promoted the IL-6-JAK-STAT3 pathway, and stem cells and immune cells could be drivers of dysplasia to OSCC. We hypothesize that 1) LSD1 upregulation during dysplasia reprograms oral tissue to invasive phenotype by acting on IL6 -signaling and induced cell types and 2) pharmacological attenuation of LSD1 reset epigenome to reverse progressive malignant preneoplasia to a noninvasive phenotype. The specific aims are 1) to determine if LSD1 collaborates with YAP to promote IL6- JAK-STAT3 network-induced invasive phenotype in preneoplasia a) to determine if LSD1 collaborates with YAP to promote IL6-JAK-STAT3 network-induced invasive phenotype in preneoplasia is syngenic and humanized PDX mouse models. b) evaluate if LSD1 reprograms preneoplasia by acting directly on H3K4me2 or H3K9me2 at STAT3, YAP, and PD-L1 promoters or indirectly through YAP/ LSD1-PD-L1 feed-forward loop to promote invasive phenotype. Aim 2 is to determine pharmacological LSD1 inhibition reverse preneoplasia by inhibiting IL6-JAK-STAT3 signaling-induced cancer stem and immune cells. We will determine if LSD1 inhibitor sensitizes clinical preneoplasia to Nivolumab in humanized PDX mice. Successful completion of the proposed project is expected to identify the mechanism by which LSD1 promotes preneoplasia via the IL6-JAK-STAT3 network or alternate pathway in genetic and clinically relevant animal models. Next, it is expected to identify if clinical anti- PD1 therapy could provide resistance to preneoplasia by inefficient blockade of LSD1 and LSD1-dependent feed-forward-loop. Overall, we expect to determine if resistant preneoplasia could be sensitized by the addition of LSD1 inhibitor.