# Cold tumours: immune deserts and exclusion

Source: https://onco.cc/pathways/immune-desert-exclusion/  
OnCo record `immune-desert-exclusion` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Pathway
- Last checked: 2026-09-09
- Tags: mechanism; mechanics-atlas
- 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.
- 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

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Tumor-infiltrating_lymphocytes
- Chen & Mellman, Elements of cancer immunity and the cancer-immune set point (Nature 2017): https://doi.org/10.1038/nature21349
- Spranger, Bao & Gajewski, Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity (Nature 2015): https://doi.org/10.1038/nature14404

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Metastatic pancreatic ductal adenocarcinoma](https://onco.cc/cancers/metastatic-pdac/), [Mismatch repair deficient (MSI-high) pancreatic ductal adenocarcinoma](https://onco.cc/cancers/msi-high-pdac/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/)
- technologies: [Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)](https://onco.cc/technologies/epigenetic-drugs/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/), [In situ vaccination](https://onco.cc/technologies/in-situ-vaccination/), [Intratumoural gene electrotransfer (IL-12 plasmid)](https://onco.cc/technologies/il12-electroporation/), [Oncolytic viruses](https://onco.cc/technologies/oncolytic-virus/), [SBRT / SABR (stereotactic radiotherapy)](https://onco.cc/technologies/sbrt/), [Single-cell & spatial profiling](https://onco.cc/technologies/single-cell-spatial/), [STING & innate immune agonists](https://onco.cc/technologies/sting-agonist/), [T-cell engagers (bispecific)](https://onco.cc/technologies/t-cell-engager/)
- targets: [B7-H4 (VTCN1)](https://onco.cc/targets/b7h4/), [CSF1R](https://onco.cc/targets/csf1r/), [CXCR4](https://onco.cc/targets/cxcr4/), [EZH2](https://onco.cc/targets/ezh2/), [FAP](https://onco.cc/targets/fap/), [IDO1](https://onco.cc/targets/ido1/), [PD-1](https://onco.cc/targets/pd1/), [PD-L1](https://onco.cc/targets/pdl1/), [PIK3CA / PI3K-alpha](https://onco.cc/targets/pik3ca/), [TGFB1](https://onco.cc/targets/tgfb1/), [VEGF / VEGFR](https://onco.cc/targets/vegf/)
- drugs: [ADU-S100 (MIW815)](https://onco.cc/drugs/adu-s100/), [Ivonescimab](https://onco.cc/drugs/ivonescimab/), [Talimogene laherparepvec](https://onco.cc/drugs/talimogene-laherparepvec/), [Tazemetostat](https://onco.cc/drugs/tazemetostat/), [Vusolimogene oderparepvec](https://onco.cc/drugs/vusolimogene-oderparepvec/)
- pathways: [cGAS-STING innate sensing](https://onco.cc/pathways/cgas-sting/), [Fibroblast activation, desmoplasia & matrix stiffness](https://onco.cc/pathways/caf-activation-desmoplasia/), [Myeloid suppression: TAMs, MDSCs & don't-eat-me signals](https://onco.cc/pathways/myeloid-suppression-axis/), [TGF-β signalling](https://onco.cc/pathways/tgf-beta/), [The cancer-immunity cycle](https://onco.cc/pathways/cancer-immunity-cycle/), [Tumour microenvironment (TME)](https://onco.cc/pathways/tumor-microenvironment/), [Wnt / β-catenin](https://onco.cc/pathways/wnt/)
- terms: [Combined positive score (CPS)](https://onco.cc/terms/cps/), [Desmoplasia (tumour stroma)](https://onco.cc/terms/desmoplasia/), [Hot vs cold tumours](https://onco.cc/terms/cold-vs-hot/), [Immune exclusion](https://onco.cc/terms/immune-exclusion/), [Immune surveillance and cancer immunoediting](https://onco.cc/terms/immune-surveillance-immunoediting/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/), [Tumour-infiltrating lymphocytes (TILs)](https://onco.cc/terms/tils/)
- bottlenecks: [Cold tumours and the immunosuppressive microenvironment](https://onco.cc/bottlenecks/b-tme-immunosuppression/), [No one can predict who responds to immunotherapy](https://onco.cc/bottlenecks/b-immunotherapy-response/)
- key papers: [Atezolizumab with or without cobimetinib versus regorafenib in previously treated metastatic colorectal cancer (IMblaze370)](https://onco.cc/key-papers/paper-eng-imblaze370-atezolizumab-cobimetinib-colorectal-lancet-oncol-2019/), [Challenges and opportunities for pancreatic cancer immunotherapy](https://onco.cc/key-papers/paper-bear-pancreatic-immunotherapy-review-cancer-cell-2020/), [Elements of cancer immunity and the cancer-immune set point](https://onco.cc/key-papers/paper-chen-nature/), [Genetic mechanisms of immune evasion in colorectal cancer](https://onco.cc/key-papers/paper-grasso-immune-evasion-colorectal-cancer-discov-2018/), [Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity](https://onco.cc/key-papers/paper-spranger-nature/), [Spatially distinct tumor immune microenvironments stratify triple-negative breast cancers](https://onco.cc/key-papers/paper-gruosso-tnbc-spatial-immune-microenvironments-jci-2019/), [Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer](https://onco.cc/key-papers/paper-feig-cxcl12-fap-cafs-t-cell-exclusion-pnas-2013/), [TGF-beta drives immune evasion in genetically reconstituted colon cancer metastasis](https://onco.cc/key-papers/paper-tauriello-tgfbeta-immune-evasion-colorectal-nature-2018/), [Unraveling triple-negative breast cancer tumor microenvironment heterogeneity: towards an optimized treatment approach](https://onco.cc/key-papers/paper-bareche-tnbc-microenvironment-jnci-2020/)

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