<p>Targeting IFN/STAT1 Pathway as a Promising Strategy to Overcome Radioresistance</p>

Abstract

The interferon (IFN)-mediated activation of the Janus kinase (JAK)-signal transducer and activator of transcription 1 (STAT1) signaling is crucial for cell sensitivity to ionizing radiation. Several preclinical studies have reported that the IFN/STAT1 pathway mediates radioresistance in the tumor microenvironment by shielding the immune responses and activating survival signaling pathways. This review focuses on the oncogenic function of the IFN/STAT1 pathway, emphasizing the major signaling pathway in radiation sensitization. Furthermore, it highlights the possibility of mediatory roles of the IFN/STAT1 pathway as a prognostic therapeutic target in the modulation of resistance to radiotherapy and chemotherapy. MicroRNA involved in the regulation of the IFN/STAT1 pathway is also discussed. A better understanding of radiation-induced IFN/STAT1 signaling will open new opportunities for the development of novel therapeutic strategies, as well as define new approaches to enhance radio-immunotherapy efficacy in the treatment of various types of cancers.

Inflammation, Fibrosis and Cancer: Mechanisms, Therapeutic Options and Challenges

“…For example, STAT1 is implicated in the development of radiotherapy resistance. STAT1 inhibitors seem to provide benefits to overcome radiotherapy resistance [296]. Additionally, the overexpression of STAT1 in both malignant breast and ovarian cancer is likely to induce tumor proliferation and other oncogenic activity [297,298].…”

Nuclear accumulation of KPNA2 impacts radioresistance through positive regulation of the PLSCR1‐STAT1 loop in lung adenocarcinoma

“…The pathway network further demonstrated that extracellular functions, cytokines, and transcriptional regulators were major factors involved in promoting radioresistance (Figure 5B). Consistently, 14 TF, including the two well‐known radioresistance‐ and/or CSC‐related genes STAT1 and SP1, 30‐35 were predicted to be the major TF involved in the transcriptional regulation of these 429 DEG according to the TRRUST database (Table ). These results support the feasibility of NGS and bioinformatic analysis for identifying the key regulators involved in KPNA2‐promoted radioresistance and CSC properties.…”

A Functional Precision Medicine Pipeline Combines Comparative Transcriptomics and Tumor Organoid Modeling to Identify Bespoke Treatment Strategies for Glioblastoma

“…In GBM, STAT1 promotes tumorigenicity, and increased expression correlates with poor patient survival [ 38 ]. Aberrant STAT1 activation triggers radioresistant signaling pathways in head and neck, renal, breast, and myeloma cancer [ 39 ]. STAT1 has also been shown to become activated by double-strand break (DSB) formation, which has implications in treatment response with standard of care DNA damaging agents (i.e., temozolomide, a DNA alkylating agent, and radiation), repair of which are mediated by upregulation of the DNA damage response (DDR) [ 40 , 41 , 42 , 43 ].…”