FOSL1 Orchestrates Epigenetic Reprogramming of Anaplastic Thyroid Cancer and Suppresses NK Cell–Mediated Antitumor Immunity

Anaplastic thyroid cancer (ATC) is the most aggressive type of thyroid cancer with survival time of only 7 to 10 months. Previous work revealed reduced proportions and cytotoxicity of NK cells in the ATC tumor microenvironment (TME). In this study, we investigated the role of super-enhancers (SE), clusters of adjacent enhancers that drive high expression of genes, in reshaping the TME in ATC. Comprehensive profiling of the SE landscapes in ATC revealed the activation of oncogenic SEs as a mechanism underlying the dedifferentiation and anaplastic transformation of thyroid cancer. An SE signature based on recurrent SEs in ATC was associated with significantly shortened overall patient survival. FOSL1 was identified as an SE-driven transcriptional factor that was crucial for epigenetic remodeling of ATC cells. Interestingly, FOSL1 bound to its own SE, promoted chromatin looping and spatial proximity of the distal SE with its promoter, and maintained its high expression, forming a positive feedback self-regulation circuit. During ATC progression, FOSL1 boosted the expression of metalloproteinases ADAM9 and MMP14 via binding to their SEs, which promoted MICA shedding from the cell surface and led to subsequent immune escape from NK-cell killing. Silencing FOSL1, ADAM9, or MMP9 sensitized ATC cells to NK cell-mediated cytotoxicity in vitro and suppressed ATC growth in vivo. Together, these findings highlight the role of FOSL1 in chromatin remodeling of ATC and in dampening cytotoxic functions of NK cells, thereby providing insights into the development of potential cancer therapeutics. SIGNIFICANCE: Profiling oncogenic super-enhancers underlying dedifferentiation and anaplastic transformation of thyroid cancer reveals FOSL1 as a driver of epigenetic remodeling and immune escape, highlighting the potential of targeting FOSL1 in anaplastic thyroid cancer.