Harnessing the STING pathway for HCC treatment

Carmen Chak-Lui Wong; Cerise Yuen-Ki Chan; Helen Do-Gai Xue; Chun-Ming Wong

doi:10.20892/j.issn.2095-3941.2025.0434

Article Figures & Data

Figures

Tables

Download figure
Open in new tab
Download powerpoint
Figure 1
Genomic instability triggers cGAS-STING signaling through cytosolic DNA accumulation. The cGAS-STING pathway serves as a cytosolic DNA sensor, initiating type I IFN and NF-κB-mediated inflammatory responses. This pathway is frequently activated in cancer through multiple mechanisms, which lead to cytosolic DNA accumulation. These mechanisms include the following: (1) defective DNA damage response and therapy-induced DNA damage generating DNA fragments; (2) presence of extrachromosomal DNA; (3) polyploidy-induced chromosome mis-segregation; (4) abnormal cell division producing micronuclei; and (5) epigenetic deregulation, which causes decondensation of repeated DNA elements and leads to DNA damage and micronuclei. Collectively, these diverse pathways of genomic instability converge to activate the cGAS-STING signaling pathway in cancer cells. cGAMP, cyclic GMP-AMP; cGAS, cyclic GMP-AMP synthase; DNA, deoxyribonucleic acid; IFN, interferon; IRF3, interferon regulatory factor 3; NF-κB, nuclear factor kappa B; SASPs, senescence-associated secretory phenotypes; STING, stimulator of interferon genes.
Download figure
Open in new tab
Download powerpoint
Figure 2
Activation of STING signaling in HCC and MASLD. The STING pathway is activated in HCC by cytosolic DNA sensing via DDX41. Cell cycle inhibitors, such as PLK4, TTK, or AURKB, induce genomic instability and micronuclei formation, triggering DDX41-STING signaling to elicit IRF3/7/NF-κB responses, which recruit anti-tumor immune cells, such as CD4⁺ T, CD8⁺ T, and NK cells. The epigenetic regulator, CAF-1, maintains chromatin stability to suppress STING activation in HCC cells, while CAF-1 knockout leads to H3.1 to H3.3 switch, which enhances genomic instability and STING-driven immunity. These approaches increase recruitment of immune cells to the tumor microenvironment and sensitize HCC to anti-PD-1 treatment. STING in myeloid cells promotes steatosis, inflammation, and fibrosis in MASLD, whereas hepatic stellate cells regulate STING stability through the NBR1/p62 axis, thus impacting CD8⁺ T cell responses and hence HCC development. Together, these microenvironmental mechanisms govern immune surveillance in HCC. CAF-1, chromatin assembly factor 1; DDX41, DEAD-box helicase 41; DNA, deoxyribonucleic acid; IFN, interferon; IRF, interferon regulatory factor; MASLD, metabolic dysfunction-associated steatotic liver disease; NBR1, neighbor of BRCA1 gene 1; NF-κB, nuclear factor kappa B; NK, natural killer; PD-1, programed death-1; PLK4, polo-like kinase 4; SASPs, senescence-associated secretory phenotypes; STING, stimulator of interferon genes; TTK, threonine and tyrosine kinase.

Tables

Figures

View popup

Table 1

Table summarizing STING activating therapies as anti-cancer treatments

Category	Mechanism of action	Examples	Combination therapy with ICB
Direct STING agonist	Binds to STING to activate IFN/NF-κB signaling	cGAMP mimics Non-nucleotide STING agonist (e.g., MSA-2) Small molecules (e.g., MK-1454 and TAK-676)	cGAMP mimics and small molecules combined with anti-PD-1 in clinical trial
Indirect STING activators	Induce DNA damage/micronuclei to trigger STING activation	Chemotheraypy/radiotherapy PARP inhibitors (e.g., olaparib) Cell cycle inhibitors (e.g., palbociclib and paclitaxel)	PARP inhibitors and cell cycle inhibitors combined with anti-PD-1 in clinical trial
Nuclease inhibitors	Block DNA/cGAMP degradation to amplify STING signaling	TREX1 inhibitors ENPP1 inhibitors	Under investigation
Nanoparticle delivery	Enhances STING agonist delivery/tumor targeting	RGD@Ce6@MSA-2@Liposome ZIF-67 nanoparticles	Combined with anti-PD-1 in clinical trial

cGAMP, cyclic GMP-AMP; DNA, deoxyribonucleic acid; ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase 1; ICB, immune checkpoint blockade; IFN, interferon; NF-κB, nuclear factor kappa B; PARP, poly(ADP-ribose) polymerase; PD-1, programed death-1; STING, stimulator of interferon genes; TREX1, three prime repair exonuclease 1.