# C5aR1 and cGAS/STING and their possible involvement in radiosensitivity of colorectal cancer **Authors:** Quoc Thao Trang Pham, Pei-Ju Lee, Nguyen Quoc Khanh Le PMC · DOI: 10.1016/j.isci.2026.115009 · iScience · 2026-02-12 ## TL;DR This paper explores how blocking C5aR1 and activating the cGAS/STING pathway may improve radiotherapy responses in colorectal cancer. ## Contribution The paper proposes a novel interaction between C5aR1 and the cGAS/STING pathway in modulating radiosensitivity in CRC. ## Key findings - C5aR1 inhibition may enhance radiosensitivity by modulating the cGAS/STING pathway. - Reduced cGAS/STING activity is linked to radioresistance in colorectal cancer. - The C5a/C5aR1 axis suppresses STING-driven IFNB1 expression in immune responses. ## Abstract Worldwide, colorectal cancer (CRC) stands as the third leading cancer in terms of both diagnosis and mortality, underscoring its significant global health impact. Enhancing radiotherapy with radiosensitizers, such as C5aR1 (complement C5a receptor 1) blockade, has shown promise in treating resistant CRC, particularly in immunologically cold tumors. However, the molecular mechanisms by which C5aR1 inhibition improves radiosensitivity remain to be clarified. Reduced cGAS/STING (cyclic guanosine monophosphate-adenosine monophosphate synthase/stimulator of interferon genes) pathway activity is linked to radioresistance, while radiotherapy-induced cGAS/STING activation increases IFNB1 (interferon beta 1) and impairs DNA repair. Conversely, the complement component 5a (C5a)/C5aR1 axis suppresses STING-driven IFNB1 expression in immune responses, suggesting their distinct regulatory effects on cancer cell radiotherapy responses. Targeting C5aR1 may therefore enhance radiosensitivity by modulating the cGAS/STING pathway. This review examines potential interactions between C5aR1 and the cGAS/STING pathway, highlighting their relevance to addressing resistance mechanisms in CRC. Immune system; Cancer ## Linked entities - **Genes:** C5AR1 (complement C5a receptor 1) [NCBI Gene 728], CGAS (cyclic GMP-AMP synthase) [NCBI Gene 115004], STING1 (stimulator of interferon response cGAMP interactor 1) [NCBI Gene 340061], IFNB1 (interferon beta 1) [NCBI Gene 3456] - **Diseases:** colorectal cancer (MONDO:0005575) ## Full-text entities - **Genes:** Egfr (epidermal growth factor receptor) [NCBI Gene 13649] {aka 9030024J15Rik, Erbb, Errb1, Errp, Wa5, wa-2}, KCTD5 (potassium channel tetramerization domain containing 5) [NCBI Gene 54442], AKT1 (AKT serine/threonine kinase 1) [NCBI Gene 100126861] {aka Akt, PKB}, STING1 (stimulator of interferon response cGAMP interactor 1) [NCBI Gene 340061] {aka ERIS, MITA, MPYS, NET23, SAVI, STING}, Prf1 (perforin 1 (pore forming protein)) [NCBI Gene 18646] {aka Pfn, Pfp, Prf-1}, Il2 (interleukin 2) [NCBI Gene 16183] {aka Il-2}, H2ax (H2A.X variant histone) [NCBI Gene 15270] {aka H2A.X, H2afx, Hist5-2ax, gammaH2ax}, Hoxc6 (homeobox C6) [NCBI Gene 15425] {aka Hox-3.3, Hox-6.1}, Birc5 (baculoviral IAP repeat-containing 5) [NCBI Gene 11799] {aka AAC-11, Api4, TIAP, survivin40}, Sirpa (signal-regulatory protein alpha) [NCBI Gene 19261] {aka Bit, CD172a, Idd13.2, P84, Ptpns1, SHP-1}, VEGFA (vascular endothelial growth factor A) [NCBI Gene 397157] {aka VEGF}, ATM (ATM serine/threonine kinase) [NCBI Gene 100101922], Pik3r1 (phosphoinositide-3-kinase regulatory subunit 1) [NCBI Gene 18708] {aka PI3K, p50alpha, p55alpha, p85alpha}, Pdcd1 (programmed cell death 1) [NCBI Gene 18566] {aka Ly101, PD-1, Pdc1}, COX2 (cytochrome c oxidase subunit II) [NCBI Gene 808504], NLRP3 (NLR family pyrin domain containing 3) [NCBI Gene 100514823], Map1lc3a (microtubule-associated protein 1 light chain 3 alpha) [NCBI Gene 66734] {aka 1010001H21Rik, 4922501H04Rik, LC3, LC3a}, Angpt1 (angiopoietin 1) [NCBI Gene 11600] {aka 1110046O21Rik, Ang-1, Ang1}, signal transducer and activator of transcription 1 [NCBI Gene 100738308], IFNB1 (interferon beta 1) [NCBI Gene 3456] {aka IFB, IFF, IFN-beta, IFNB}, TBK1 (TANK binding kinase 1) [NCBI Gene 100125828], Il18 (interleukin 18) [NCBI Gene 16173] {aka Igif, Il-18}, Bcl2l1 (BCL2-like 1) [NCBI Gene 12048] {aka Bcl(X)L, Bcl-XL, Bcl2l, BclX, bcl-x, bcl2-L-1}, CDK1 (cyclin dependent kinase 1) [NCBI Gene 983] {aka CDC2, CDC28A, P34CDC2}, KDR (kinase insert domain receptor) [NCBI Gene 397311] {aka FLK-1}, Irf3 (interferon regulatory factor 3) [NCBI Gene 54131] {aka C920001K05Rik, IRF-3}, Cxcl9 (C-X-C motif chemokine ligand 9) [NCBI Gene 17329] {aka CMK, Mig, MuMIG, Scyb9, crg-10}, FOSL1 (FOS like 1, AP-1 transcription factor subunit) [NCBI Gene 8061] {aka FRA, FRA1, fra-1}, LOC100153783 (ovalbumin) [NCBI Gene 100153783], CFB (complement factor B) [NCBI Gene 629] {aka AHUS4, ARMD14, BF, BFD, CFAB, CFBD}, Trp53-ps (transformation related protein 53, pseudogene) [NCBI Gene 22060], Tnfrsf13c (tumor necrosis factor receptor superfamily, member 13c) [NCBI Gene 72049] {aka 2010006P15Rik, BAFF-R, Baffr, Bcmd, Bcmd-1, Bcmd1}, Havcr2 (hepatitis A virus cellular receptor 2) [NCBI Gene 171285] {aka TIM-3, Tim3, Timd3}, Cd4 (CD4 antigen) [NCBI Gene 12504] {aka L3T4, Ly-4}, IFNA1 (interferon alpha 1) [NCBI Gene 3439] {aka IFL, IFN, IFN-ALPHA, IFN-alphaD, IFNA13, IFNA@}, Il6 (interleukin 6) [NCBI Gene 16193] {aka Il-6}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, TRAF6 (TNF receptor associated factor 6) [NCBI Gene 396629], Slc7a11 (solute carrier family 7 (cationic amino acid transporter, y+ system), member 11) [NCBI Gene 26570] {aka 9930009M05Rik, sut, xCT}, CD4 (CD4 molecule) [NCBI Gene 920] {aka CD4mut, IMD79, Leu-3, OKT4D, T4}, CTLA4 (cytotoxic T-lymphocyte associated protein 4) [NCBI Gene 397286], Akt1 (Akt serine/threonine kinase 1) [NCBI Gene 11651] {aka Akt, LTR-akt, PKB, PKB/Akt, PKBalpha, Rac}, TNF (tumor necrosis factor) [NCBI Gene 397086] {aka TNFSF2, TNFa}, Cgas (cyclic GMP-AMP synthase) [NCBI Gene 214763] {aka E330016A19Rik, Mb21d1}, Rbm6 (RNA binding motif protein 6) [NCBI Gene 19654] {aka 4930506F14Rik, Def-3, NY-LU-12, g16, mKIAA4015}, Foxp3 (forkhead box P3) [NCBI Gene 20371] {aka JM2, scurfin, sf}, MAPK8 (mitogen-activated protein kinase 8) [NCBI Gene 396610] {aka JNK, JNK1}, RNF8 (ring finger protein 8) [NCBI Gene 9025] {aka hRNF8}, STING1 (stimulator of interferon response cGAMP interactor 1) [NCBI Gene 100217389] {aka STING, TMEM173}, Chek2 (checkpoint kinase 2) [NCBI Gene 50883] {aka CHK2, Cds1, HUCDS1, Rad53}, Gpbar1 (G protein-coupled bile acid receptor 1) [NCBI Gene 227289] {aka BG37, GPCR, GPR131, M-BAR, TGR5}, Traf6 (TNF receptor-associated factor 6) [NCBI Gene 22034] {aka 2310003F17Rik, C630032O20Rik}, PREX2 [NCBI Gene 100156424], IFNB1 (interferon beta 1) [NCBI Gene 445459] {aka IFN-beta, IFNb}, Lamb3 (laminin, beta 3) [NCBI Gene 16780], Ifng (interferon gamma) [NCBI Gene 15978] {aka IFN-g, If2f, Ifg}, Lig4 (ligase IV, DNA, ATP-dependent) [NCBI Gene 319583] {aka 5830471N16Rik, tiny}, Prdm15 (PR domain containing 15) [NCBI Gene 114604] {aka C21orf83, E130018M06Rik, ORF62, Zfp298}, Prkdc (protein kinase, DNA activated, catalytic polypeptide) [NCBI Gene 19090] {aka DNA-PKcs, DNAPDcs, DNAPK, DNPK1, DOXNPH, HYRC1}, Lag3 (lymphocyte-activation gene 3) [NCBI Gene 16768] {aka CD223, LAG-3, Ly66} - **Diseases:** hepatocellular carcinoma (MESH:D006528), necrosis (MESH:D009336), glioblastoma (MESH:D005909), squamous malignancies (MESH:D002294), cognitive impairments (MESH:D003072), infectious (MESH:D003141), hypoxia (MESH:D000860), colon and rectal adenocarcinoma (MESH:D003110), IBD (MESH:D015212), hypoxic (MESH:D002534), breast cancer (MESH:D001943), lymph node metastasis (MESH:D008207), cytotoxic T lymphocyte (MESH:D015458), colorectal tumorigenesis (MESH:D063646), ovarian tumors (MESH:D010051), infection (MESH:D007239), Cancer (MESH:D009369), colitis (MESH:D003092), cytotoxic (MESH:D064420), rectal cancer (MESH:D012004), neuroinflammation (MESH:D000090862), inflammation (MESH:D007249), T cell dysfunction (MESH:C536780), liver metastasis (MESH:D009362), complement (MESH:D007153), meningococcal sepsis (MESH:D008589), CRC (MESH:D015179) - **Chemicals:** riluzole (MESH:D019782), NAD (MESH:D009243), berzosertib (MESH:C000598331), TLC388 (MESH:C549429), Mitoxantrone (MESH:D008942), talazoparib (MESH:C586365), Oxaliplatin (MESH:D000077150), PMX205 (MESH:C504156), SHP099 (MESH:C000609471), dextran sulfate sodium (MESH:D016264), 5-FU (MESH:D005472), ATP (MESH:D000255), MTX (MESH:D008727), LY294002 (MESH:C085911), niraparib (MESH:C545685), lipid (MESH:D008055), PGE2 (MESH:D015232), PMX53 (MESH:C438957), galunisertib (MESH:C557799), honokiol (MESH:C005499), peroxide (MESH:D010545), CX-5461 (MESH:C557717), cGAMP (MESH:C584311), IRIN (MESH:D000077146), serine (MESH:D012694), palbociclib (MESH:C500026), BEZ235 (MESH:C531198), Avacopan (MESH:C000620232), GTP (MESH:D006160), DSS (-), poly(ADP-ribose) (MESH:D011064), AOM (MESH:D001397), oxygen (MESH:D010100) - **Species:** Fusobacterium nucleatum (species) [taxon 851], Mus musculus (house mouse, species) [taxon 10090], Bacteria Latreille et al. 1825 (Bacteria stick insect, genus) [taxon 629395], Homo sapiens (human, species) [taxon 9606] - **Mutations:** V600E - **Cell lines:** SW48 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_1724), HT29 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0320), SW1463 — Homo sapiens (Human), Rectal adenocarcinoma, Cancer cell line (CVCL_1718), DLD-1 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0248), RKO — Homo sapiens (Human), Colon carcinoma, Cancer cell line (CVCL_0504), SW1116 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0544), HRA-19 — Homo sapiens (Human), Rectal adenocarcinoma, Cancer cell line (CVCL_2508), SW837 — Homo sapiens (Human), Rectal adenocarcinoma, Cancer cell line (CVCL_1729), LOVO — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0399), HCT116 — Homo sapiens (Human), Colon carcinoma, Cancer cell line (CVCL_0291), HCT15 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0292), SW480 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0546), SW620 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0547), CaCo-2 — Homo sapiens (Human), Colon adenocarcinoma, Cancer cell line (CVCL_0025) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12969006/full.md ## Figures 3 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12969006/full.md ## References 244 references — full list in the complete paper: https://tomesphere.com/paper/PMC12969006/full.md --- Source: https://tomesphere.com/paper/PMC12969006