Background

Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for approximately 1.79 million fatalities annually [1]. Non-small cell lung cancer (NSCLC) accounts for 85% of cases, with low survival rates with existing treatments. In recent years, NSCLC therapy has undergone an enormous shift since the identification of immunological checkpoints and the subsequent development of immune checkpoint inhibitors (ICIs) [2]. Immunocheckpoint blockade (ICB) targeting the programmed cell death-1/programmed death-ligand1 (PD-1/PD-L1) pathway has become a new standard treatment for NSCLC, improving survival rates either when used alone or in conjunction with conventional chemotherapy [3]. Despite recent developments in immunotherapy, more research is still required to fully comprehend the biology of immune-responsive subsets.

The immune system may be stimulated, and the tumor response to immunotherapy may be improved, by DNA damage, which can be intrinsic due to tumor genomic instability or exacerbated as a result of DNA-damaging treatments [4]. The cGAS-STING signaling pathway is a crucial cytosolic DNA sensing mechanism in vivo, involved in inducing the expression of type I interferons (IFNs) and influencing the body's immune response in controlling pathogen infection, tumor immunity, and autoimmune disorders. cGAS contains an extremely conserved nucleotidyltransferase domain that may detect double-stranded DNA (dsDNA) released into the cytosol [5]. This cGAS-STING signaling in turn triggers IFN I and cytokine response [6–8]. Since aberrant DNA is particularly prominent in cancer as a result of its release from necrotic cells and DNA leakage into the cytosol of cancer cells [9], cGAS signaling may trigger IFN I synthesis, immunological activation, and cancer cell apoptosis. Consequently, downregulating the cGAS-STING pathway would make it possible for cancer cells to avoid immune recognition and response. Furthermore, this pathway's activation can upregulate PD-L1, inhibiting cytotoxic T lymphocyte (CTLs) activity [10]; mutant p53 has also been shown to suppress downstream signaling from cGAS/STING pathway, thereby enabling immune evasion [11].

We studied the cGAS-STING pathway using systems biology, a holistic approach to decode complex, dynamic biological systems with numerous interrelationships and interactions that occur within the confines of time, physiology, and space [12–14]. One crucial tool in systems biology is mathematical modeling, which determines how biological system components interact to produce intricate dynamic behavior. Computational experiments using mathematical models to simulate biological systems could provide valuable insights into the driven mechanisms [15,16]. A unique systems biology toolbox is offered within the MATLAB framework, providing researchers with a versatile platform to explore biological systems, design algorithms, and create simulation tools [17–19]. In this study, we used mathematical modeling to address a knowledge gap by reconstructing the cGAS-STING signaling pathway using MATLAB and understanding its regulatory and molecular drivers through iterative model simulations and data analysis. This included the identification and validation of statistical parameters of the model, such as sensitivity, principal components, and model reduction. Altogether, these studies present a mathematical model as a framework to redesign complex signaling networks; modulating such signaling axes could allow better therapeutic intervention.