Despite great interest in their clinical use, little is known regarding molecular targets important for response to HDACibased cancer therapy. Identification of HDACi targets, therefore, may lead to the discovery of new biomarkers of disease status, improve the way patients are selected for HDACi-based therapy and potentially guide the development of new drugs. The loss of Fas function in neoplastic cells is thought to be an important mechanism both for resistance to certain chemotherapeutic agents and for tumor escape from immune attack. Our earlier work led to the identification of interferon regulatory factor-8 as a positive regulator of response to Fas-mediated killing of non-hematopoietic tumor cells. We further observed that low levels of both Fas and IRF-8 expression by tumor cells correlated with more rapid tumor growth. These data suggested that IRF-8 down-regulation contributes to tumor progression via CPI-613 increased resistance to apoptosis, such as Fas-mediated killing. Although IRF-8 was originally discovered as an IFN-c inducible transcription factor essential for normal myelopoiesis and as a tumor suppressor of certain leukemias, our findings revealed a new functional role for IRF-8 in non-hematopoietic malignancies. However, the mechanisms GSK2118436 involved in IRF-8 downregulation in tumor cells remained unclear. We reasoned that rescue of IRF-8 expression in tumor cells may improve responses to anti-neoplastic therapies, such as chemotherapy or biologic -based immunotherapy. Several studies now demonstrate that IRF-8 expression in various human cancers and tumor cell lines can be down-regulated by epigenetic mechanisms. It has also been shown that Trichostatin A, a potent pan-HDACi, can reinstate Fas sensitivity in tumor cells. However, the molecular mechanisms for HDACi-induced apoptosis of tumor cells are not well-defined. We hypothesized that IRF-8 expression in tumor cells is an important molecular component for their susceptibility to HDACi-induced apoptosis. To test our central hypothesis, we focused on two questions: 1) Is IRF-8 expression in tumor cells required for their susceptibility to Fas-mediated killing induced by HDACi? and 2) Is IRF-8 expression required for HDACi to promote antitumor effects in tumor-bearing mice? Overall, our data show that HDACi enhances IRF-8 expression in tumor cells involving STAT1, and promotes Fas-mediated killing and antitumor activity via an IRF8-dependent pathway. Therefore, IRF-8 expression in tumors may represent a unique molecular marker for predicting response to HDACi-based therapies. We next examined the effects of TSA or DP on IRF-8 expression using a highly aggressive metastatic variant of CMS4 cells, termed CMS4.met.sel. This subline was established as a tumor escape variant following CD8 + CTL adoptive immunotherapy. Immune resistance correlated with a significant reduction in both Fas and IRF-8 expression in response to IFN-c.