Cancer Cells Exploit Sublethal Apoptotic Signaling as an Adaptive Mechanism to Evade Immune Surveillance and Drive Relapse

Abstract

Oncogene-targeted therapies often result in significant early tumor reductions; nevertheless, they are eventually constrained by relapse due to minimum residual disease (MRD). This review presents new evidence demonstrating a paradigm shift in the understanding of treatment resistance, with a focus on the non-apoptotic, adaptive roles of apoptotic proteins in cancer persister cells. We demonstrate the mechanisms through which sub-lethal apoptotic signalling in this temporary, drug-tolerant population is utilised for the survival and proliferation of these cells. An important finding is that caspases can activate the DNA fragmentation factor B (DFFB) as a dual mechanism. A model is proposed in which sublethal apoptotic signalling within persister cancer cells activates DFFB, then potentially induces ATF3 that leads to inhibition of type I interferon signalling and promotes tumour regrowth. DFFB activation is achieved by upregulation of activation transcription factor 3 (ATF3) during early stages of stress. The identification of a connection between therapy-induced genotoxic stress and the immune escape mechanism is provided by the DFFB-ATF3 molecular network. This allows persister cells to avoid dormancy caused by IFN production. We have changed the known view of DFFB from a molecule that causes cell death to a key regulator of an adaptive, prosurvival response that leads to eventual relapse. Thus, focusing on this axis offers a viable treatment strategy to eliminate minimal residual disease by concurrently blocking adaptive mutagenesis and reinstating intrinsic immunemediated growth regulation, providing an innovative combinatorial approach to avert relapse and enhance long-term outcomes.