{"entity":{"id":"immune-desert-exclusion","kind":"pathway","name":"Cold tumours: immune deserts and exclusion","aka":[],"tldr":"Tumours come in three immune weathers: inflamed (T cells inside, checkpoint drugs work), excluded (T cells stuck at the edge), and desert (no T cells at all). Most common cancers are excluded or desert, and turning them 'hot' is the central problem of immunotherapy.","summary":"Deserts arise from low antigenicity (low TMB, MHC loss), failed priming (few BATF3+ cDC1, low CCL4 because of tumour-intrinsic WNT/β-catenin signalling; PTEN loss; MYC-driven CD47/PD-L1), and absent chemokines (CXCL9/10 silenced by EZH2 and DNMT1). Exclusion arises from stroma: TGF-β-activated CAFs and dense collagen (Mariathasan 2018), CXCL12 from FAP+ fibroblasts, abnormal VEGF-driven vessels lacking adhesion molecules, and myeloid barriers. Inflamed tumours still fail through PD-L1, exhaustion and Tregs. Converters: radiotherapy and chemotherapy (immunogenic death, STING), oncolytic viruses and in situ vaccines, STING agonists (systemic versions disappointed), anti-VEGF and TGF-β blockade (bintrafusp alfa failed), FAP/CXCR4 targeting, epigenetic priming to restore chemokines, and antigen-independent killers (engagers, CAR-T) that do not need a hot tumour. Gene signatures (T-cell inflamed GEP, TIS) and spatial pathology grade the weather.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Tumor-infiltrating_lymphocytes","links":[{"label":"Chen & Mellman, Elements of cancer immunity and the cancer-immune set point (Nature 2017)","url":"https://doi.org/10.1038/nature21349"},{"label":"Spranger, Bao & Gajewski, Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity (Nature 2015)","url":"https://doi.org/10.1038/nature14404"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":["pancreatic"],"sections":[],"technologies":["checkpoint-inhibitor","oncolytic-virus","in-situ-vaccination","sting-agonist","sbrt","epigenetic-drugs","t-cell-engager","single-cell-spatial","il12-electroporation"],"targets":["pd1","pdl1","vegf","fap","ezh2","csf1r","cxcr4","pik3ca"],"drugs":["talimogene-laherparepvec","vusolimogene-oderparepvec","ivonescimab","adu-s100","tazemetostat"],"companies":[],"institutions":[],"pathways":["tgf-beta","wnt","cgas-sting","tumor-microenvironment","cancer-immunity-cycle","myeloid-suppression-axis"],"terms":["cold-vs-hot","immune-exclusion","tils","tmb","cps","desmoplasia"],"trials":[],"people":[],"bottlenecks":["b-immunotherapy-response","b-tme-immunosuppression"],"keyPapers":["paper-chen-nature","paper-spranger-nature"],"journals":[],"dependsOn":[],"notes":[],"analogy":"Three kinds of town: one where the police already patrol the streets (inflamed), one where they mill about outside a wall (excluded), and one with no police station at all (desert). Removing the officers' handcuffs (PD-1 blockade) only helps in the first; the second needs a gate, the third needs recruitment.","nodes":[{"id":"ag","label":"Low TMB, MHC loss","x":12,"y":12},{"id":"wnt","label":"β-catenin, PTEN loss → no cDC1","x":12,"y":40,"targetId":"pik3ca"},{"id":"chemo","label":"CXCL9/10 silenced (EZH2)","x":12,"y":68,"targetId":"ezh2"},{"id":"desert","label":"Immune desert","x":42,"y":40},{"id":"tgf","label":"TGF-β CAFs, collagen","x":72,"y":12,"targetId":"fap"},{"id":"vess","label":"Abnormal vessels (VEGF)","x":72,"y":40,"targetId":"vegf"},{"id":"excl","label":"Immune exclusion","x":92,"y":60},{"id":"hot","label":"Inflamed → PD-1 response","x":42,"y":90,"targetId":"pd1"},{"id":"conv","label":"RT, STING, viruses, vaccines","x":12,"y":92},{"id":"myeloid","label":"Myeloid barrier","x":72,"y":68,"targetId":"csf1r"}],"edges":[{"from":"ag","to":"desert","type":"activates"},{"from":"wnt","to":"desert","type":"activates"},{"from":"chemo","to":"desert","type":"activates"},{"from":"tgf","to":"excl","type":"activates"},{"from":"vess","to":"excl","type":"activates"},{"from":"myeloid","to":"excl","type":"activates"},{"from":"desert","to":"hot","type":"inhibits"},{"from":"excl","to":"hot","type":"inhibits"},{"from":"conv","to":"hot","type":"activates"},{"from":"conv","to":"desert","type":"inhibits"}],"interventions":["Radiotherapy, immunogenic chemotherapy and TOP1 ADCs to seed antigen and STING signalling; oncolytic viruses (T-VEC, RP1) and in situ vaccination","Anti-VEGF and PD-1×VEGF bispecifics open the vessel gate; FAP-, CXCR4- and TGF-β-directed agents (mostly modest so far)","Epigenetic priming (EZH2, DNMT inhibitors) to restore chemokines; STING agonists intratumourally","Bypass the weather: T-cell engagers, CAR-T, TCR-T and vaccines that bring or make their own T cells"]},"route":"/pathways/immune-desert-exclusion/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"metastatic-pdac","kind":"cancer","name":"Metastatic pancreatic ductal adenocarcinoma","route":"/cancers/metastatic-pdac/"},{"id":"msi-high-pdac","kind":"cancer","name":"Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma","route":"/cancers/msi-high-pdac/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"}],"technology":[{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"in-situ-vaccination","kind":"technology","name":"In situ vaccination","route":"/technologies/in-situ-vaccination/"},{"id":"il12-electroporation","kind":"technology","name":"Intratumoural gene electrotransfer (IL-12 plasmid)","route":"/technologies/il12-electroporation/"},{"id":"oncolytic-virus","kind":"technology","name":"Oncolytic viruses","route":"/technologies/oncolytic-virus/"},{"id":"sbrt","kind":"technology","name":"SBRT / SABR (stereotactic radiotherapy)","route":"/technologies/sbrt/"},{"id":"single-cell-spatial","kind":"technology","name":"Single-cell & spatial profiling","route":"/technologies/single-cell-spatial/"},{"id":"sting-agonist","kind":"technology","name":"STING & innate immune agonists","route":"/technologies/sting-agonist/"},{"id":"t-cell-engager","kind":"technology","name":"T-cell engagers (bispecific)","route":"/technologies/t-cell-engager/"}],"target":[{"id":"b7h4","kind":"target","name":"B7-H4 (VTCN1)","route":"/targets/b7h4/"},{"id":"csf1r","kind":"target","name":"CSF1R","route":"/targets/csf1r/"},{"id":"cxcr4","kind":"target","name":"CXCR4","route":"/targets/cxcr4/"},{"id":"ezh2","kind":"target","name":"EZH2","route":"/targets/ezh2/"},{"id":"fap","kind":"target","name":"FAP","route":"/targets/fap/"},{"id":"ido1","kind":"target","name":"IDO1","route":"/targets/ido1/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"},{"id":"pik3ca","kind":"target","name":"PIK3CA / PI3K-alpha","route":"/targets/pik3ca/"},{"id":"tgfb1","kind":"target","name":"TGFB1","route":"/targets/tgfb1/"},{"id":"vegf","kind":"target","name":"VEGF / VEGFR","route":"/targets/vegf/"}],"drug":[{"id":"adu-s100","kind":"drug","name":"ADU-S100 (MIW815)","route":"/drugs/adu-s100/"},{"id":"ivonescimab","kind":"drug","name":"Ivonescimab","route":"/drugs/ivonescimab/"},{"id":"talimogene-laherparepvec","kind":"drug","name":"Talimogene laherparepvec","route":"/drugs/talimogene-laherparepvec/"},{"id":"tazemetostat","kind":"drug","name":"Tazemetostat","route":"/drugs/tazemetostat/"},{"id":"vusolimogene-oderparepvec","kind":"drug","name":"Vusolimogene oderparepvec","route":"/drugs/vusolimogene-oderparepvec/"}],"pathway":[{"id":"cgas-sting","kind":"pathway","name":"cGAS-STING innate sensing","route":"/pathways/cgas-sting/"},{"id":"caf-activation-desmoplasia","kind":"pathway","name":"Fibroblast activation, desmoplasia & matrix stiffness","route":"/pathways/caf-activation-desmoplasia/"},{"id":"myeloid-suppression-axis","kind":"pathway","name":"Myeloid suppression: TAMs, MDSCs & don't-eat-me signals","route":"/pathways/myeloid-suppression-axis/"},{"id":"tgf-beta","kind":"pathway","name":"TGF-β signalling","route":"/pathways/tgf-beta/"},{"id":"cancer-immunity-cycle","kind":"pathway","name":"The cancer-immunity cycle","route":"/pathways/cancer-immunity-cycle/"},{"id":"tumor-microenvironment","kind":"pathway","name":"Tumour microenvironment (TME)","route":"/pathways/tumor-microenvironment/"},{"id":"wnt","kind":"pathway","name":"Wnt / β-catenin","route":"/pathways/wnt/"}],"term":[{"id":"cps","kind":"term","name":"Combined positive score (CPS)","route":"/terms/cps/"},{"id":"desmoplasia","kind":"term","name":"Desmoplasia (tumour stroma)","route":"/terms/desmoplasia/"},{"id":"cold-vs-hot","kind":"term","name":"Hot vs cold tumours","route":"/terms/cold-vs-hot/"},{"id":"immune-exclusion","kind":"term","name":"Immune exclusion","route":"/terms/immune-exclusion/"},{"id":"immune-surveillance-immunoediting","kind":"term","name":"Immune surveillance and cancer immunoediting","route":"/terms/immune-surveillance-immunoediting/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"},{"id":"tils","kind":"term","name":"Tumour-infiltrating lymphocytes (TILs)","route":"/terms/tils/"}],"bottleneck":[{"id":"b-tme-immunosuppression","kind":"bottleneck","name":"Cold tumours and the immunosuppressive microenvironment","route":"/bottlenecks/b-tme-immunosuppression/"},{"id":"b-immunotherapy-response","kind":"bottleneck","name":"No one can predict who responds to immunotherapy","route":"/bottlenecks/b-immunotherapy-response/"}],"paper":[{"id":"paper-eng-imblaze370-atezolizumab-cobimetinib-colorectal-lancet-oncol-2019","kind":"paper","name":"Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370)","route":"/key-papers/paper-eng-imblaze370-atezolizumab-cobimetinib-colorectal-lancet-oncol-2019/"},{"id":"paper-bear-pancreatic-immunotherapy-review-cancer-cell-2020","kind":"paper","name":"Challenges and opportunities for pancreatic cancer immunotherapy","route":"/key-papers/paper-bear-pancreatic-immunotherapy-review-cancer-cell-2020/"},{"id":"paper-chen-nature","kind":"paper","name":"Elements of cancer immunity and the cancer-immune set point","route":"/key-papers/paper-chen-nature/"},{"id":"paper-grasso-immune-evasion-colorectal-cancer-discov-2018","kind":"paper","name":"Genetic mechanisms of immune evasion in colorectal cancer","route":"/key-papers/paper-grasso-immune-evasion-colorectal-cancer-discov-2018/"},{"id":"paper-spranger-nature","kind":"paper","name":"Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity","route":"/key-papers/paper-spranger-nature/"},{"id":"paper-gruosso-tnbc-spatial-immune-microenvironments-jci-2019","kind":"paper","name":"Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers","route":"/key-papers/paper-gruosso-tnbc-spatial-immune-microenvironments-jci-2019/"},{"id":"paper-feig-cxcl12-fap-cafs-t-cell-exclusion-pnas-2013","kind":"paper","name":"Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer","route":"/key-papers/paper-feig-cxcl12-fap-cafs-t-cell-exclusion-pnas-2013/"},{"id":"paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018","kind":"paper","name":"TGF-beta drives immune evasion in genetically reconstituted colon cancer metastasis","route":"/key-papers/paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018/"},{"id":"paper-bareche-tnbc-microenvironment-jnci-2020","kind":"paper","name":"Unraveling triple-negative breast cancer tumor microenvironment heterogeneity: towards an optimized treatment approach","route":"/key-papers/paper-bareche-tnbc-microenvironment-jnci-2020/"}]}}