{"doi":"10.1042/ebc20253006","title":"The cGAS-STING pathway in cancer immunity: dual roles, therapeutic strategies, and clinical challenges","abstract":"<jats:p>The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway is a crucial component of the host’s innate immunity and plays a central role in detecting cytosolic double-stranded DNA from endogenous and exogenous sources. Upon activation, cGAS synthesizes cGAMP, which binds to STING, triggering a cascade of immune responses, including the production of type I interferons and pro-inflammatory cytokines. In the context of cancers, the cGAS-STING pathway can exert dual roles: on the one hand, it promotes anti-tumor immunity by enhancing antigen presentation, stimulating T-cell responses, and inducing direct tumor cell apoptosis. On the other hand, chronic activation, particularly in tumors with chromosomal instability, can lead to immune suppression and tumor progression. Persistent cGAS-STING signaling results in the up-regulation of immune checkpoint molecules such as PD-L1, contributing to immune evasion and metastasis. Consequently, anti-tumor strategies targeting the cGAS-STING pathway have to consider the balance of immune activation and the immune tolerance caused by chronic activation. This review explores the mechanisms underlying both the anti-tumor and protumor roles of the cGAS-STING pathway, with a focus on potential therapeutic approaches, and the challenges faced in their clinical application, along with corresponding solutions.</jats:p>","journal":"Essays in Biochemistry","year":2025,"id":622855,"datarank":0.5709993734655481,"base_score":3.8066624897703196,"endowment":3.8066624897703196,"self_citation_contribution":0.5709993734655481,"citation_network_contribution":0.0,"self_endowment_contribution":0.5709993734655481,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":44,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1609524,"name":"Wenbo Gao","orcid":null,"position":1,"is_corresponding":false},{"id":747201,"name":"Jonathan F. Lovell","orcid":"0000-0002-8626-3033","position":2,"is_corresponding":false},{"id":427751,"name":"Honglin Jin","orcid":"0000-0002-4398-9539","position":3,"is_corresponding":false},{"id":14808,"name":"Jing Huang","orcid":"0000-0001-7116-5847","position":4,"is_corresponding":false},{"id":1609523,"name":"Beilei Yue","orcid":"0009-0002-5891-1299","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"The cGAS-STING pathway in cancer immunity: dual roles, therapeutic strategies, and clinical challenges","abstract":"<jats:p>The cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS-STING) pathway is a crucial component of the host’s innate immunity and plays a central role in detecting cytosolic double-stranded DNA from endogenous and exogenous sources. Upon activation, cGAS synthesizes cGAMP, which binds to STING, triggering a cascade of immune responses, including the production of type I interferons and pro-inflammatory cytokines. In the context of cancers, the cGAS-STING pathway can exert dual roles: on the one hand, it promotes anti-tumor immunity by enhancing antigen presentation, stimulating T-cell responses, and inducing direct tumor cell apoptosis. On the other hand, chronic activation, particularly in tumors with chromosomal instability, can lead to immune suppression and tumor progression. Persistent cGAS-STING signaling results in the up-regulation of immune checkpoint molecules such as PD-L1, contributing to immune evasion and metastasis. Consequently, anti-tumor strategies targeting the cGAS-STING pathway have to consider the balance of immune activation and the immune tolerance caused by chronic activation. This review explores the mechanisms underlying both the anti-tumor and protumor roles of the cGAS-STING pathway, with a focus on potential therapeutic approaches, and the challenges faced in their clinical application, along with corresponding solutions.</jats:p>","is_dataset_classified":null,"base_score":3.7376696182833684,"endowment":3.7376696182833684,"datacite_reuse_total":0,"file_count":0,"downloads":0,"views":0,"has_version_chain":false,"is_dataset":false,"is_oa":false,"pmid":"40052963","pmcid":"PMC12204001","openalex_id":"https://openalex.org/W4408225535","authors":[],"funders":[],"total_grants":0,"fwci":16.5811,"citation_percentile":0.99500588,"influential_citations":0,"citation_trend":[{"year":2025,"count":17},{"year":2026,"count":24}],"oa_status":"hybrid","license":"cc-by","oa_locations":[{"url":"https://portlandpress.com/essaysbiochem/article-pdf/doi/10.1042/EBC20253006/969742/ebc-2025-3006.pdf","host_type":"journal"},{"url":"https://portlandpress.com/essaysbiochem/article-pdf/doi/10.1042/EBC20253006/969742/ebc-2025-3006.pdf","host_type":"publisher"},{"url":"https://portlandpress.com/essaysbiochem/article-pdf/69/02/63/969742/ebc-2025-3006.pdf","host_type":"publisher"},{"url":"https://doi.org/10.1042/ebc20253006","host_type":"journal"},{"url":"https://pubmed.ncbi.nlm.nih.gov/40052963","host_type":"repository"},{"url":"https://www.ncbi.nlm.nih.gov/pmc/articles/12204001","host_type":"repository"},{"url":"https://europepmc.org/articles/PMC12204001","host_type":"Europe_PMC"},{"url":"https://europepmc.org/articles/PMC12204001?pdf=render","host_type":"Europe_PMC"}],"fields_of_study":["interferon and immune responses","Viral Infections and Vectors","Inflammasome and immune disorders","Humans","Nucleotidyltransferases","Neoplasms","Membrane Proteins","Signal Transduction","Animals","Immunity, Innate","Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase","STING Protein"],"mesh_terms":["STING Protein","Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase","Animals","Humans","Immunity, Innate","Membrane Proteins","Neoplasms","Nucleotidyltransferases","Signal Transduction"],"keywords":["Sting","Immunity","Dual (grammatical number)","Cancer","Biology","Medicine","Computational biology","Immunology","Immune system","Internal medicine","Engineering","Cancer Immunotherapy","Chromosomal Instability","Targeted Therapies","Immune Evasion","Cgas-sting Pathway"],"sdg_mappings":[{"sdg_number":0,"sdg_label":"Good health and well-being"}],"linked_datasets":[],"clinical_trials":[],"software_tools":[],"database_accessions":[],"source":"live","citation_network_status":"fetched"},"created_at":"2026-08-03T21:19:09.212275Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}