Elucidating DNA Damage-Dependent Immune System Activation

Abstract

The DNA-damage response (DDR) network and the immune system are significant mechanisms linked to the normal functioning of living organisms. Extensive observations suggest that agents that damage the DNA can boost immunity in various ways, some of which may be useful for immunotherapeutic applications. Indeed, the immune system can be activated by the DDR network through a number of different mechanisms, such as via (a) an increase in the tumor neoantigen burden, (b) the induction of the stimulator of interferon genes pathway, (c) the triggering of immunogenic cell death, (d) an increase in antigen presentation as a result of the augmented expression of the major histocompatibility complex type I molecule, (e) modification of the cytokine milieu in the tumor microenvironment, and (f) altered expression of the programmed cell death ligand-1. Together, the DDR network may improve the effect of immunostimulatory anticancer agents and provide a basis for devising more efficient treatment strategies, such as combinatorial therapies of DDR targeting drugs and immunomodulators. Here, the molecular mechanisms underlying the immune system's activation by DDR are summarized, along with some of their possible uses in cancer treatment.

Keywords: DNA-damage response (DDR); immune checkpoint inhibitor; immune system; immunogenic cell death (ICD); major histocompatibility complex type I (MHC-I); programmed cell death ligand-1 (PD-L1); stimulator of interferon genes (STING); tumor mutational burden (TMB); tumor neoantigen burden (TNB).

Figure 1

Immunogenic cell death (ICD) and its role in antitumor immunity. Upon exposure to an ICD inducer, tumor cells undergo immunogenic cell death characterized by the release and surface exposure of damage-associated molecular patterns (DAMPs), which include calreticulin (CALR), adenosine triphosphate (ATP) and high-mobility group box 1 (HMGB1). These DAMPs collectively stimulate antigen engulfment and dendritic cell (DC) maturation, enabling effective tumor antigen presentation to T cells. The subsequent T-cell recruitment and activation culminate in a robust antitumor immune response and tumor cell destruction. Figure produced using “BioRender.com (accessed on 23 May 2025)”.

Figure 2

The role of the cGAS-STING pathway in health and cancer therapy. Various stressors such as viral infection, anticancer therapies or radiation can lead to the accumulation of double-stranded DNA (dsDNA) fragments in the cytosol. These fragments are sensed by cyclic GMP–AMP synthase (cGAS), which catalyzes the production of cyclic GMP–AMP (cGAMP). cGAMP binds to and activates the adaptor protein STING (stimulator of interferon genes), triggering its phosphorylation. Activated STING recruits and activates TANK-binding kinase 1 (TBK1), which subsequently phosphorylates the transcription factor IRF3 (interferon regulatory factor 3). Phosphorylated IRF3 translocates into the nucleus, where it induces the expression of type I interferons. These interferons play a critical role in promoting an immune response, contributing to antiviral defense and antitumor immunity. Figure produced using “BioRender.com (accessed on 23 May 2025)”.

Figure 3

The PD-1/PD-L1 signaling pathway in the onset, progression and management of cancer. (A) The interaction of PD-1 and PD-L1 facilitates tumor survival. Specifically, the interaction between PD-1 and its ligand, PD-L1, leads to T-cell and malignant-cell engagement, suppresses downstream T-cell receptor (TCR) signaling and effectively inhibits T-cell activation, which impedes antitumor immune responses. (B) Activation of T cells and cancer cell death. The administration of ICIs, such as anti-PD-1 antibodies, can restore the function of exhausted T cells, thereby enhancing their cytotoxic activity and facilitating the elimination of tumor cells. (C) Regulation of PD-1/PD-L1 expression by various pathways. Multiple intracellular signaling cascades, including the JAK/STAT, MAPK, WNT, PI3K/AKT and NF-κΒ pathways, are implicated in regulating PD-L1 expression and contributing to tumor immune-evasion mechanisms. Figure produced using “BioRender.com (accessed on 24 May 2025)”.

Figure 4

DDR-induced immunogenic modulation. DNA-damaging agents induce a variety of DNA lesions, and if repair is unsuccessful, they may increase the tumor mutational burden (TMB). An elevated TMB promotes the generation of neoantigens, which are presented on MHC class I molecules to T-cell receptors (TCR), enhancing T-cell recognition. DNA damage also results in cytosolic DNA accumulation, triggering STING pathway activation and the release of damage-associated molecular patterns (DAMPs), thereby promoting immunogenic cell death (ICD). Concurrently, cancer cells may upregulate PD-L1 expression to evade immune responses through a PD-1/PD-L1 interaction. Immune checkpoint inhibitors (ICIs) block this pathway, restoring T-cell function and reinforcing their antitumor activity. This illustration highlights how DDR-targeting therapies can synergize with ICIs to potentiate cancer immunotherapy. Figure produced using “BioRender.com (accessed on 23 May 2025)”.