# Combining advanced radiotherapy techniques and immunotherapy: immunomodulatory mechanisms and clinical prospects **Authors:** Linsen Zhou, Qianyi Liu, Yongze He, Ying Tang, Shuotong Liu, Xiaobin Wang, Shiyan Shen, Jialin Ji, Zhen Liu, Xianhu Zeng, Jiangping Li PMC · DOI: 10.3389/fimmu.2026.1737661 · Frontiers in Immunology · 2026-02-18 ## TL;DR This review discusses how combining advanced radiotherapy techniques with immunotherapy can boost the immune system's ability to fight cancer and improve treatment outcomes. ## Contribution The paper systematically explores the immunomodulatory mechanisms and clinical potential of combining advanced radiotherapy techniques with immunotherapy. ## Key findings - Advanced radiotherapy activates antitumor immunity through immunogenic cell death and cGAS–STING pathway activation. - These techniques synergize with immunotherapy to enhance local and systemic tumor control, including the abscopal effect. - Compared to conventional radiotherapy, advanced techniques better protect normal tissues and modulate the tumor microenvironment. ## Abstract This review systematically explores the mechanisms and clinical prospects of combining advanced radiotherapy techniques—including stereotactic body radiotherapy, FLASH radiotherapy, proton therapy, carbon ion radiotherapy, and spatially fractionated radiotherapy—with immunotherapy. It elucidates how radiotherapy activates systemic antitumor immunity by inducing immunogenic cell death, activating the cGAS–STING pathway, upregulating MHC-I expression, and remodeling the tumor microenvironment. These mechanisms synergize with immune checkpoint inhibitors to enhance both local and systemic tumor control, including the abscopal effect. Compared with conventional radiotherapy, these advanced techniques leverage precise dose distributions, ultra-high dose rates, or the Bragg Peak physical properties to better protect normal tissues, mitigate radiation-induced lymphopenia, and favorably modulate the tumor microenvironment. Although preclinical studies and emerging clinical trials support the feasibility and efficacy of such combinations, further large-scale, well-designed clinical trials are required to validate their optimal application strategies and long-term benefits. ## Linked entities - **Proteins:** CGAS (cyclic GMP-AMP synthase), STING1 (stimulator of interferon response cGAMP interactor 1), MHC-I (BOLA class I histocompatibility antigen, alpha chain BL3-7) ## Full-text entities - **Genes:** CCL5 (C-C motif chemokine ligand 5) [NCBI Gene 6352] {aka D17S136E, RANTES, SCYA5, SIS-delta, SISd, TCP228}, IL4 (interleukin 4) [NCBI Gene 3565] {aka BCGF-1, BCGF1, BSF-1, BSF1, IL-4}, IL18 (interleukin 18) [NCBI Gene 3606] {aka IGIF, IL-18, IL-1g, IL1F4}, 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}, Cea (carcinoembryonic antigen gene family) [NCBI Gene 111518], CALR (calreticulin) [NCBI Gene 811] {aka CALR1, CRT, HEL-S-99n, RO, SSA, cC1qR}, Cxcl15 (C-X-C motif chemokine ligand 15) [NCBI Gene 20309] {aka Il8, Scyb15, lungkine, weche}, MACF1 (microtubule actin crosslinking factor 1) [NCBI Gene 23499] {aka ABP620, ACF7, KIAA0754, LIS9, Lnc-PMIF, MACF}, CCL11 (C-C motif chemokine ligand 11) [NCBI Gene 6356] {aka SCYA11}, Irf3 (interferon regulatory factor 3) [NCBI Gene 54131] {aka C920001K05Rik, IRF-3}, STAT1 (signal transducer and activator of transcription 1) [NCBI Gene 6772] {aka CANDF7, IMD31A, IMD31B, IMD31C, ISGF-3, STAT91}, Cxcl9 (C-X-C motif chemokine ligand 9) [NCBI Gene 17329] {aka CMK, Mig, MuMIG, Scyb9, crg-10}, P2RX7 (purinergic receptor P2X 7) [NCBI Gene 5027] {aka P2X7}, NOS2 (nitric oxide synthase 2) [NCBI Gene 4843] {aka HEP-NOS, INOS, NOS, NOS2A}, Hmgb1 (high mobility group box 1) [NCBI Gene 15289] {aka HMG-1, Hmg1, SBP-1, p30}, Jak2 (Janus kinase 2) [NCBI Gene 16452] {aka Fd17}, BRCA1 (BRCA1 DNA repair associated) [NCBI Gene 100049662], TP53 (tumor protein p53) [NCBI Gene 7157] {aka BCC7, BMFS5, LFS1, P53, TRP53}, GZMB (granzyme B) [NCBI Gene 3002] {aka C11, CCPI, CGL-1, CGL1, CSP-B, CSPB}, CXCL9 (C-X-C motif chemokine ligand 9) [NCBI Gene 4283] {aka CMK, Humig, MIG, SCYB9, crg-10}, LRP1 (LDL receptor related protein 1) [NCBI Gene 4035] {aka A2MR, APOER, APR, CD91, DDH3, IGFBP-3R}, STING1 (stimulator of interferon response cGAMP interactor 1) [NCBI Gene 340061] {aka ERIS, MITA, MPYS, NET23, SAVI, STING}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, IL2RA (interleukin 2 receptor subunit alpha) [NCBI Gene 3559] {aka CD25, IDDM10, IL2R, IMD41, TCGFR, p55}, Tnfsf10 (tumor necrosis factor (ligand) superfamily, member 10) [NCBI Gene 22035] {aka A330042I21Rik, APO-2L, Ly81, TL2, Tnlg6a, Trail}, Il2 (interleukin 2) [NCBI Gene 16183] {aka Il-2}, IL10 (Interleukin 10 level) [NCBI Gene 103158318], ICAM1 (intercellular adhesion molecule 1) [NCBI Gene 3383] {aka BB2, CD54, P3.58}, CD274 (CD274 molecule) [NCBI Gene 29126] {aka ADMIO5, B7-H, B7H1, PD-L1, PDCD1L1, PDCD1LG1}, CD80 (CD80 molecule) [NCBI Gene 941] {aka B7, B7-1, B7.1, BB1, CD28LG, CD28LG1}, STAT1 (signal transducer and activator of transcription 1) [NCBI Gene 396655], CGAS (cyclic GMP-AMP synthase) [NCBI Gene 100516408] {aka MB21D1}, HMGB1 (high mobility group box 1) [NCBI Gene 3146] {aka HMG-1, HMG1, HMG3, SBP-1}, Hspa1b (heat shock protein family A (Hsp70) member 1B) [NCBI Gene 15511] {aka HSP70B1, Hsp70, Hsp70-1, Hsp70.1, hsp68}, JAK2 (Janus kinase 2) [NCBI Gene 3717] {aka JTK10}, Ifng (interferon gamma) [NCBI Gene 15978] {aka IFN-g, If2f, Ifg}, IDO1 (indoleamine 2,3-dioxygenase 1) [NCBI Gene 3620] {aka IDO, IDO-1, INDO}, IL2 (interleukin 2) [NCBI Gene 3558] {aka IL-2, TCGF, lymphokine}, MYD88 (MYD88 innate immune signal transduction adaptor) [NCBI Gene 4615] {aka IMD68, MYD88D, WM1}, ITGAL (integrin subunit alpha L) [NCBI Gene 3683] {aka CD11A, EV6, HNA-5, LFA-1, LFA1A}, ARG1 (arginase 1) [NCBI Gene 383], STING1 (stimulator of interferon response cGAMP interactor 1) [NCBI Gene 100217389] {aka STING, TMEM173}, FOXP3 (forkhead box P3) [NCBI Gene 50943] {aka AIID, DIETER, IPEX, JM2, PIDX, XPID}, IRF1 (interferon regulatory factor 1) [NCBI Gene 3659] {aka IMD117, IRF-1, MAR}, NFKB1 (nuclear factor kappa B subunit 1) [NCBI Gene 4790] {aka CVID12, EBP-1, KBF1, NF-kB, NF-kB1, NF-kappa-B1}, CD4 (CD4 molecule) [NCBI Gene 920] {aka CD4mut, IMD79, Leu-3, OKT4D, T4}, S100a8 (S100 calcium binding protein A8 (calgranulin A)) [NCBI Gene 20201] {aka 60B8Ag, B8Ag, CFAg, CP-10, Caga, MRP8}, EIF2AK4 (eukaryotic translation initiation factor 2 alpha kinase 4) [NCBI Gene 440275] {aka GCN2, PVOD2}, Cgas (cyclic GMP-AMP synthase) [NCBI Gene 214763] {aka E330016A19Rik, Mb21d1}, Stat3 (signal transducer and activator of transcription 3) [NCBI Gene 20848] {aka 1110034C02Rik, Aprf}, CXCL8 (C-X-C motif chemokine ligand 8) [NCBI Gene 3576] {aka GCP-1, GCP1, IL8, LECT, LUCT, LYNAP}, CSF1 (colony stimulating factor 1) [NCBI Gene 1435] {aka CSF-1, MCSF, PG-M-CSF}, CD28 (CD28 molecule) [NCBI Gene 940] {aka IMD123, Tp44}, CCL2 (chemokine (C-C motif) ligand 2) [NCBI Gene 397422] {aka MCP-1}, CXCL16 (C-X-C motif chemokine ligand 16) [NCBI Gene 58191] {aka CXCLG16, SR-PSOX, SRPSOX}, CSF2 (colony stimulating factor 2) [NCBI Gene 1437] {aka CSF, GMCSF}, AHR (aryl hydrocarbon receptor) [NCBI Gene 196] {aka FVH3, RP85, bHLHe76}, Sting1 (stimulator of interferon response cGAMP interactor 1) [NCBI Gene 72512] {aka 2610307O08Rik, ERIS, MPYS, Mita, STING, STING-beta} - **Diseases:** CFRT (MESH:D054144), SFRT (MESH:D008569), colon adenocarcinoma 38 (MESH:D003110), RCC (MESH:D002292), NSCLC (MESH:D002289), glioblastoma (MESH:D005909), HNSCC (MESH:D000077195), esophageal cancer (MESH:D004938), intestinal injury (MESH:D007410), renal cancer (MESH:D007680), necrosis (MESH:D009336), Merkel cell carcinoma (MESH:D015266), HCC (MESH:D006528), stage III (MESH:D062706), ovarian cancer (MESH:D010051), pulmonary fibrosis (MESH:D011658), Lewis lung carcinoma 1 (MESH:D018827), Triple-Negative Breast Cancer (MESH:D064726), breast cancer (MESH:D001943), leukopenia (MESH:D007970), thymic injury (MESH:D013953), MDSCs (OMIM:601308), cytotoxicity (MESH:D064420), neck mass (MESH:D006258), cancer (MESH:D009369), papillary adenocarcinoma (MESH:D000231), peritoneal (MESH:D010538), cervical adenocarcinoma (MESH:D000230), lymphopenia (MESH:D008231), bone marrow dysfunction (MESH:D001855), myeloma (MESH:D009101), lung cancer (MESH:D008175), fibrosarcoma (MESH:D005354), skin toxicity (MESH:D012871), Urothelial Carcinoma (MESH:D014523), pancreatic cancer (MESH:D010190), colorectal cancer (MESH:D015179), Small Cell Lung Cancer (MESH:D055752), cervical cancer (MESH:D002583), deaths (MESH:D003643), pain (MESH:D010146), bone metastases (MESH:D009362), SCLC (MESH:D018288), fibrosis (MESH:D005355), glioma (MESH:D005910), melanoma (MESH:D008545), prostate cancer (MESH:D011471), inflammation (MESH:D007249) - **Chemicals:** ROS (MESH:D017382), calcium (MESH:D002118), neon (MESH:D009356), Trp (MESH:D014364), Kyn (MESH:D007737), Cobalt-60 (MESH:C000615395), ipilimumab (MESH:D000074324), Nivolumab (MESH:D000077594), cabozantinib (MESH:C558660), atezolizumab (MESH:C000594389), Durvalumab (MESH:C000613593), sunitinib (MESH:D000077210), ATP (MESH:D000255), L-arginine (MESH:D001120), carbon (MESH:D002244), pembrolizumab (MESH:C582435), cGAMP (MESH:C584311), K+ (MESH:D011188), adenosine (MESH:D000241), GTP (MESH:D006160), CFRT (-) - **Species:** Sus scrofa (pig, species) [taxon 9823], Homo sapiens (human, species) [taxon 9606], Felis catus (cat, species) [taxon 9685], Mus musculus (house mouse, species) [taxon 10090], Rattus norvegicus (brown rat, species) [taxon 10116], Danio rerio (leopard danio, species) [taxon 7955] - **Mutations:** A2A - **Cell lines:** MC38 — Mus musculus (Mouse), Mouse colon adenocarcinoma, Cancer cell line (CVCL_B288), LLC1 — Mus musculus (Mouse), Malignant tumors of the mouse pulmonary system, Cancer cell line (CVCL_4358), C57BL/6 — Mus musculus (Mouse), Transformed cell line (CVCL_C0MU) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12956806/full.md ## Figures 4 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12956806/full.md ## References 216 references — full list in the complete paper: https://tomesphere.com/paper/PMC12956806/full.md --- Source: https://tomesphere.com/paper/PMC12956806