# Research on the Mechanism of “Cold Tumor” Formation and Immunotherapy for Its Transformation into “Hot Tumor” **Authors:** Liang Zhou, Jia Zhou, Zhengyi Wang PMC · DOI: 10.32604/or.2026.069317 · Oncology Research · 2026-02-24 ## TL;DR This paper explores how to convert 'cold tumors' into 'hot tumors' to improve immunotherapy effectiveness by understanding immune evasion and using new technologies. ## Contribution The paper systematically explains mechanisms of immune evasion in cold tumors and proposes advanced therapeutic strategies using nanotechnology, gene editing, and AI. ## Key findings - Cold tumors can be transformed into hot tumors through modulation of the immune microenvironment. - Combining AI, genomics, and biotechnology offers new prospects for cold tumor treatment. - Nanotechnology and gene editing are promising tools for enhancing immunotherapy response. ## Abstract A clear goal in cold tumor research is to identify strategies for converting them into immunologically ‘hot’ tumors with enhanced immune cell infiltration and activity, thereby improving their responsiveness to immunotherapy. The genesis of cold tumors is exceedingly intricate. In recent times, as the analysis of this phenomenon has been pursued with greater depth, a suite of advanced diagnostic and therapeutic technologies has surfaced. These novel approaches and tactics are anticipated to modulate the tumor immune microenvironment across various dimensions, thereby facilitating the advancement of personalized and precise treatment modalities for cold tumors. The present article addresses the challenge of diminished therapeutic responsiveness to “cold tumors” within clinical settings. It systematically elucidates the multi-faceted regulatory mechanisms underlying immune evasion in cold tumors and offers a detailed analysis of advanced therapeutic strategies that incorporate nanotechnology, gene editing, and artificial intelligence methodologies. Furthermore, the future development trends of immunotherapy were explored in greater depth. It was posited that the convergence of artificial intelligence, multidimensional genomics, and emerging biotechnologies has presented positive prospects for the treatment of cold tumors, and has offered a theoretical foundation and technical framework for the transformation of cold tumors into “hot tumors”. ## Full-text entities - **Genes:** B2M (beta-2-microglobulin) [NCBI Gene 397033], CDK8 (cyclin dependent kinase 8) [NCBI Gene 1024] {aka IDDHBA, K35}, FN1 (fibronectin 1) [NCBI Gene 2335] {aka CIG, ED-B, FINC, FN, FNZ, GFND}, Cd247 (CD247 antigen) [NCBI Gene 12503] {aka 4930549J05Rik, A430104F18Rik, Cd3, Cd3-eta, Cd3-zeta, Cd3h}, CCL21 (C-C motif chemokine ligand 21) [NCBI Gene 6366] {aka 6Ckine, CKb9, ECL, SCYA21, SLC, TCA4}, CD86 (CD86 molecule) [NCBI Gene 942] {aka B7-2, B7.2, B70, BU63, CD28LG2, CD86 v6}, CTLA4 (cytotoxic T-lymphocyte associated protein 4) [NCBI Gene 1493] {aka ALPS5, CD, CD152, CELIAC3, CTLA-4, GRD4}, MTOR (mechanistic target of rapamycin kinase) [NCBI Gene 2475] {aka FRAP, FRAP1, FRAP2, RAFT1, RAPT1, SKS}, PAGE5 (PAGE family member 5) [NCBI Gene 90737] {aka CT16, CT16.1, CT16.2, GAGEE1, PAGE-5}, Il4ra (interleukin 4 receptor, alpha) [NCBI Gene 16190] {aka CD124, Il4r}, BTLA (B and T lymphocyte associated) [NCBI Gene 151888] {aka BTLA1, CD272}, TP63 (tumor protein p63) [NCBI Gene 8626] {aka AIS, B(p51A), B(p51B), EEC3, KET, LMS}, HCAR1 (hydroxycarboxylic acid receptor 1) [NCBI Gene 27198] {aka FKSG80, GPR104, GPR81, HCA1, LACR1, TA-GPCR}, Erbb2 (erb-b2 receptor tyrosine kinase 2) [NCBI Gene 13866] {aka Erbb-2, HER-2, HER2, Neu, c-erbB2, c-neu}, HMBS (hydroxymethylbilane synthase) [NCBI Gene 3145] {aka ENCEP, LENCEP, PBG-D, PBGD, PORC, UPS}, TIGIT (T cell immunoreceptor with Ig and ITIM domains) [NCBI Gene 201633] {aka VSIG9, VSTM3, WUCAM}, Gpc3 (glypican 3) [NCBI Gene 14734] {aka OCI-5}, CD8A (CD8 subunit alpha) [NCBI Gene 925] {aka CD8, CD8alpha, IMD116, Leu2, p32}, CD40 (CD40 molecule) [NCBI Gene 958] {aka Bp50, CDW40, TNFRSF5, p50}, HDAC9 (histone deacetylase 9) [NCBI Gene 9734] {aka HD7, HD7b, HD9, HDAC, HDAC7B, HDAC9B}, JAK1 (Janus kinase 1) [NCBI Gene 3716] {aka AIIDE, JAK1A, JAK1B, JTK3}, WWP2 (WW domain containing E3 ubiquitin protein ligase 2) [NCBI Gene 11060] {aka AIP2, WWp2-like}, CD274 (CD274 molecule) [NCBI Gene 574058] {aka PDL1}, TGFB1 (transforming growth factor beta 1) [NCBI Gene 7040] {aka CAEND1, CED, DPD1, IBDIMDE, LAP, TGF-beta1}, ADRA2B (adrenoceptor alpha 2B) [NCBI Gene 151] {aka ADRA2L1, ADRA2RL1, ADRARL1, ALPHA2BAR, FAME2, alpha-2BAR}, LAG3 (lymphocyte activating 3) [NCBI Gene 3902] {aka CD223}, Il4 (interleukin 4) [NCBI Gene 16189] {aka BSF-1, Il-4}, KRAS (KRAS proto-oncogene, GTPase) [NCBI Gene 3845] {aka 'C-K-RAS, C-K-RAS, CFC2, K-RAS2A, K-RAS2B, K-RAS4A}, NFE2L2 (NFE2 like bZIP transcription factor 2) [NCBI Gene 4780] {aka IMDDHH, NRF2, Nrf-2}, PDCD1 (programmed cell death 1) [NCBI Gene 100533201], CTNNB1 (catenin beta 1) [NCBI Gene 1499] {aka CTNNB, EVR7, MRD19, NEDSDV, armadillo}, Msln (mesothelin) [NCBI Gene 56047] {aka C-ERC, MPF}, IL7 (interleukin 7) [NCBI Gene 3574] {aka IL-7, IMD130}, STUB1 (STIP1 homology and U-box containing protein 1) [NCBI Gene 10273] {aka CHIP, HSPABP2, NY-CO-7, SCA48, SCAR16, SDCCAG7}, EGFR (epidermal growth factor receptor) [NCBI Gene 1956] {aka ERBB, ERBB1, ERRP, HER1, NISBD2, NNCIS}, SCO2 (synthesis of cytochrome C oxidase 2) [NCBI Gene 9997] {aka CEMCOX1, ECGF1, Gliostatin, MC4DN2, MYP6, PD-ECGF}, CD4 (CD4 molecule) [NCBI Gene 920] {aka CD4mut, IMD79, Leu-3, OKT4D, T4}, IL13 (interleukin 13) [NCBI Gene 3596] {aka IL-13, P600}, FLT4 (fms related receptor tyrosine kinase 4) [NCBI Gene 2324] {aka CHTD7, FLT-4, FLT41, LMPH1A, LMPHM1, PCL}, EBI3 (Epstein-Barr virus induced 3) [NCBI Gene 10148] {aka IL-27B, IL27B, IL35B}, CD19 (CD19 molecule) [NCBI Gene 930] {aka B4, CVID3}, PIK3CB (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) [NCBI Gene 5291] {aka P110BETA, PI3K, PI3KBETA, PIK3C1}, HLA-G (major histocompatibility complex, class I, G) [NCBI Gene 3135] {aka MHC-G}, CXCR5 (C-X-C motif chemokine receptor 5) [NCBI Gene 643] {aka BLR1, CD185, MDR15}, Nr1i3 (nuclear receptor subfamily 1, group I, member 3) [NCBI Gene 12355] {aka CAR, CAR-beta, Care2, ESTM32, MB67}, MIR21 (microRNA 21) [NCBI Gene 406991] {aka MIRN21, hsa-mir-21, miR-21, miRNA21}, IL2 (interleukin 2) [NCBI Gene 3558] {aka IL-2, TCGF, lymphokine}, CYP3A4 (cytochrome P450 family 3 subfamily A member 4) [NCBI Gene 1576] {aka CP33, CP34, CYP3A, CYP3A3, CYPIIIA3, CYPIIIA4}, VN1R17P (vomeronasal 1 receptor 17 pseudogene) [NCBI Gene 441931] {aka GPCR}, TMEM127 (transmembrane protein 127) [NCBI Gene 55654], IL12A (interleukin 12A) [NCBI Gene 3592] {aka CLMF, IL-12A, NFSK, NKSF1, P35}, ANCR (Angelman syndrome chromosome region) [NCBI Gene 282], CD274 (CD274 molecule) [NCBI Gene 29126] {aka ADMIO5, B7-H, B7H1, PD-L1, PDCD1L1, PDCD1LG1}, EPAS1 (endothelial PAS domain protein 1) [NCBI Gene 2034] {aka ECYT4, HIF2A, HLF, MOP2, PASD2, bHLHe73}, Fcer1g (Fc receptor, IgE, high affinity I, gamma polypeptide) [NCBI Gene 14127] {aka CD23, FcR-gamma, FcR[g], FcRgamma, Fce1g, FcepsilonRI}, IFNG (interferon gamma) [NCBI Gene 3458] {aka IFG, IFI, IMD69}, STAR (steroidogenic acute regulatory protein) [NCBI Gene 6770] {aka STARD1}, HIF1A (hypoxia inducible factor 1 subunit alpha) [NCBI Gene 3091] {aka HIF-1-alpha, HIF-1A, HIF-1alpha, HIF1, HIF1-ALPHA, MOP1}, GLS (glutaminase) [NCBI Gene 2744] {aka AAD20, CASGID, DEE71, EIEE71, GAC, GAM}, SUSD6 (sushi domain containing 6) [NCBI Gene 9766] {aka DRAGO, KIAA0247} - **Diseases:** Tumor associated antigens (MESH:C535887), liver metastasis (MESH:D009362), immunodeficiency diseases (MESH:D007153), DCPs (MESH:D054740), leukemia (MESH:D007938), colon cancer (MESH:D015179), viral infection (MESH:D014777), cold (MESH:D000067390), irAEs (MESH:D002318), immune system (MESH:D007154), colitis (MESH:D003092), cytotoxicity (MESH:D064420), lactic toxicity (MESH:C565446), MDSCs (OMIM:601308), CRS (MESH:D000080424), Tertiary Lymphoid (MESH:D000072717), breast cancer (MESH:D001943), mesothelioma (MESH:D008654), liver (MESH:D017093), LNP (MESH:D015223), lung, breast, colon, ovarian, pancreatic, and prostate cancers (MESH:D010051), amino acid metabolism disorders (MESH:D000592), hepatocellular carcinoma (MESH:D006528), pancreatic lesions (MESH:D010182), TAM (MESH:D000072716), glioblastoma (MESH:D005909), CCC (MESH:D002292), solid (MESH:D018250), PDAC (MESH:D021441), T cell inflammation (MESH:D007249), prostate cancer (MESH:D011471), MOF (MESH:D013651), melanoma (MESH:D008545), Hot Tumor (MESH:D019584), pancreatic cancer (MESH:D010190), lung cancer (MESH:D008175), Cold Tumors (MESH:D009369), graft-vs.-host disease (MESH:D006086), LARC (MESH:D012004), autoimmune diseases (MESH:D001327), breast and gastric cancers (MESH:D013274), hypoxic (MESH:D002534), pneumonia (MESH:D011014), tumorigenesis (MESH:D063646), AML (MESH:D015470), metabolic (MESH:D008659), hematologic tumor (MESH:D019337), fever (MESH:D005334), kidney cancer (MESH:D007680), squamous cell carcinoma (MESH:D002294), Non-small cell lung cancer (MESH:D002289), Hypoxia (MESH:D000860) - **Chemicals:** silicon (MESH:D012825), ARV-471 (-), tivozanib (MESH:C553176), NO (MESH:D009614), H2S (MESH:D006862), unsaturated fatty acid (MESH:D005231), Vorinostat (MESH:D000077337), Pembrolizumab (MESH:C582435), Amino Acid (MESH:D000596), solanine (MESH:D012992), Cetuximab (MESH:D000068818), arginine (MESH:D001120), Fatty Acid (MESH:D005227), GSH (MESH:D005978), Glutamine (MESH:D005973), Lipid (MESH:D008055), nivolumab (MESH:D000077594), tryptophan (MESH:D014364), Dupilumab (MESH:C582203), Glucose (MESH:D005947), ROS (MESH:D017382), Metal (MESH:D008670), pyruvate (MESH:D019289), Adenosine (MESH:D000241), lactic acid (MESH:D019344), TAK-243 (MESH:C000622638), MOF (MESH:D000073396), Entinostat (MESH:C118739), water (MESH:D014867), Nucleotide (MESH:D009711), Ipilimumab (MESH:D000074324), sorafenib (MESH:D000077157), Kyn (MESH:D007737), 4-HNE (MESH:C027576), bevacizumab (MESH:D000068258) - **Species:** Homo sapiens (human, species) [taxon 9606], Gallus gallus (bantam, species) [taxon 9031], Mus musculus (house mouse, species) [taxon 10090], Saccharomyces cerevisiae (baker's yeast, species) [taxon 4932] - **Mutations:** G12D - **Cell lines:** MDA-MB-231 — Homo sapiens (Human), Breast adenocarcinoma, Cancer cell line (CVCL_0062), B16-F10 — Mus musculus (Mouse), Mouse melanoma, Cancer cell line (CVCL_0159), MCF-7 — Homo sapiens (Human), Invasive breast carcinoma of no special type, Cancer cell line (CVCL_0031) ## Full text _Full body text omitted from this summary view._ Fetch the complete paper as Markdown: https://tomesphere.com/paper/PMC12963659/full.md ## Figures 3 figures with captions in the complete paper: https://tomesphere.com/paper/PMC12963659/full.md ## References 186 references — full list in the complete paper: https://tomesphere.com/paper/PMC12963659/full.md --- Source: https://tomesphere.com/paper/PMC12963659