The endoplasmic reticulum (ER) drives anti-tumor mechanisms by: 1) destroying oxidized or improperly folded proteins, via activation of Unfolded Protein Response and ER-assisted degradation; and 2) staging the formation of autophagosomes, which promote the degradation of damaged organelle or cytoplasmic entities. We have identified a novel non-STAT signaling pathway, where in an endoplasmic resident transcription factor ATF6, in association with the transcription factor C/EBP-b regulates the IFN-g-induced expression of death-associated protein kinase 1(DAPK1), a major suppressor of tumor metastasis and promoter of apoptosis and autophagy. IFN-g-induced proteolytic processing of ATF6 and a MAPK-dependent phosphorylation of C/EBP-b are essential for transcription of DAPK1. The molecular and genetic bases for the progression of chronic lymphocytic leukemia (CLL) are poorly understood. We show that a failure of IFN-γ activated collaboration between C/EBP-b and/or ATF6 in CLL results in a loss of growth control via autophagy. Restoration of ATF6 or C/EBP-b in to respective defective-primary tumor cells, re-establishes DAPK1 expression and enforces sensitivity to IFN-g and other clinically used therapeutics. Furthermore, we also show that this pathway is also defective in a number of lung cancers. Together, these results identified a novel ER-dependent tumor suppressive pathway controlled by IFN-g. Details of these pathway will be discussed.