Inhibiting LSD1 unlocks retinoid AP-1 programming to activate epithelial immunity and skin tumor suppression [CreERTRNAseq]

Lysine-specific demethylase 1 (LSD1; KDM1A) orchestrates context-dependent chromatin programs, yet its role in epithelial immunity remains largely unknown. Here, we identify LSD1 as a central brake on retinoid- and AP-1–driven enhancer activation in epidermis and demonstrate that its inhibition induces anti-tumor immunity. While epidermal LSD1 is required during development, acute loss or topical inhibition in adult skin is tolerated and triggers coordinated expression of retinoic acid signaling, lipid remodeling, and chemokine induction pathways. CUT&RUN profiling reveals that LSD1 occupies enhancer regions enriched for AP-1 motifs at retinoid metabolism, lipid homeostasis, and immune genes. LSD1 loss increases H3K4me1/2 and gene activation at these sites, licensing a poised AP-1–retinoid program. Single-cell spatial analyses show that discrete keratinocyte subsets initiate retinoid signaling to recruit dendritic cells and activate CD4⁺ T cell responses. Topical LSD1 inhibition suppresses cutaneous squamous cell carcinoma in two models while amplifying keratinocyte–immune crosstalk. Functional perturbations reveal that retinoid signaling partially contributes, whereas CD4⁺ T cells are essential for tumor control. These findings define LSD1 as a master repressor of epithelial immune competence and nominate LSD1 inhibition as a therapeutic strategy to activate retinoid–AP-1 enhancer circuits and drive CD4-dependent tumor immunity in skin cancer.