Interleukin-33 (IL-33) promotes DNA damage-resistance in lung cancer

Resistance to DNA damage is one of the primary mechanisms by which tumor cells evade the effects of standard chemotherapeutic agents and radiotherapy. Dynamic and complex interactions between the tumor microenvironment (TME) and tumor cells critically influence the DNA damage response. Interleukin-33 (IL-33) is a multifunctional cytokine secreted at high levels in response to cellular damage and stress. Recently, increasing evidence has suggested that IL-33 plays a key role in promoting the therapeutic resistance of tumors. However, the actual source of IL-33 during cancer therapy and how IL-33 contributes to a resistant TME remain incompletely understood. In this study, we found that both cancer-associated fibroblasts (CAFs) and tumor cells treated with DNA damage-inducing agents expressed and secreted high levels of IL-33, subsequently leading to enhanced DNA damage repair efficacy. Mechanistically, nuclear IL-33 primarily functions as a transcriptional co-activator of homologous recombination repair (HRR) genes, whereas the active form of IL-33 can drive the non-homologous end joining (NHEJ) pathway via the canonical IL-33/ST2 axis. Overall, we demonstrated that IL-33 plays a key role in mediating a DNA damage-resistant TME, which could represent a potential therapeutic vulnerability in chemoresistant cancer cells Overall design: A549 cells stably expressing vector control, IL-33-full length and IL-33-cytokine domain were generated by lentivirus infection and puromycin selection, then cells were treated with or with out 1 µM doxorubicin for 48 h . Then total RNA was extracted to assess the differentially expressed genes after ARv7 levels changes. For CUT&Tag assay, A549 cells stably overexpressing IL-33-full length and IL-33-cytokine domain were subjected to CUT&Tag analysis to further examine the nuclear function of IL-33.