Anthony J. Vasquez Sr. — Delaware Valley University, Doylestown, PA, USA
Corresponding author: vasquezaj3921@delval.edu
Context-Specific Innate Immune Evasion via VDAC1 Gate-Jamming in Microsatellite-Stable Colorectal Cancer: A Three-Cohort Transcriptomic Analysis
Published on Research Square — February 26, 2026. DOI: 10.21203/rs.3.rs-8935902/v1
85-95% of colorectal cancer patients carry microsatellite-stable (MSS) tumors and derive no benefit from immune checkpoint inhibitors. This paper proposes that VDAC1 gate-jamming — suppression of VDAC1 oligomerization by HK-II, Bcl-xL, and mitochondrial cholesterol — silences the cGAS-STING innate immune signal that checkpoint inhibitors require to function, and tests this hypothesis across three cohorts.
Manuscript: paper/gjs_manuscript.docx | paper/gjs_manuscript.md
| Analysis | Cohort | n | Result |
|---|---|---|---|
| S1 | TCGA pan-cancer | 10,071 | Null — cross-cancer confounds mask signal |
| S2 | COADREAD MSS/TP53-wt | 209 | 5 Bonferroni-significant immune correlations |
| S3 | IMvigor210 atezolizumab | 348 | Null — wrong tumor type, wrong treatment mechanism |
The two nulls define the framework's boundary. The signal appears precisely where the biology predicts it should — and not where it shouldn't.
| Marker | Spearman rho | p_bonf | Direction |
|---|---|---|---|
| HAVCR2 (TIM-3) | -0.349 | 5 x 10^-6 | Down — T cell absence, not exhaustion |
| TREX1 | +0.315 | 7 x 10^-5 | Up — belt-and-suspenders DNA erasure |
| CXCL10 | -0.231 | 0.015 | Down — suppressed IFN-gamma signaling |
| STING ratio | -0.216 | 0.034 | Down — shift to immunosuppressive profile |
| cGAS | -0.208 | 0.049 | Down |
tGJS = 0.40 x norm(HK2) + 0.30 x norm(BCL2L1) + 0.30 x norm(TSPO)
A three-gene transcriptomic proxy for the physical Gate-Jamming Score:
GJS = f_HKII x 0.40 + f_BclxL x 0.30 + [Chol]/[CL]_norm x 0.30
Where f_HKII and f_BclxL are the fractions of VDAC1 occupied by hexokinase-II and Bcl-xL respectively (measurable by proximity ligation assay), and [Chol]/[CL] is the outer mitochondrial membrane cholesterol-to-cardiolipin ratio (measurable by lipidomics).
Three independent AI analytical systems (Claude Opus, Gemini Pro, Grok) converged on the same three-layer intervention from the same data without cross-exposure:
- VDAC1 gate-opener — displace HK-II (methyl jasmonate, clotrimazole) to restore mtDNA release and cGAS-STING activation
- DNA/cGAMP eraser inhibitor — block TREX1 or ENPP1 to sustain the innate signal
- Checkpoint blockade — amplify the adaptive response now that T cells are being recruited
vdac-pharmacology-atlas/
├── paper/
│ ├── gjs_manuscript.md # Manuscript source
│ ├── gjs_manuscript.docx # Submission file
│ ├── build_manuscript_docx.py # Reproducible build script
│ ├── supplementary_S1_tcga_boundary_analysis.md
│ ├── supplementary_S2_coadread_mss_stratification.md
│ ├── supplementary_S3_imvigor210.md
│ ├── supplementary-S1-tcga-boundary-analysis.docx
│ ├── supplementary-S2-coadread-mss.docx
│ ├── supplementary-S3-imvigor210.docx
│ └── vpa_cbd_hepatotoxicity_alert.md # Pharmacovigilance alert
├── analysis/
│ ├── tcga_gjs/
│ │ ├── compute_tgjs.py # S1: pan-cancer pipeline
│ │ ├── compute_tgjs_coadread_mss.py # S2: COADREAD MSS stratified
│ │ ├── data/
│ │ │ └── coadread_mss/ # S2 results + strata summary
│ │ └── figures/
│ │ ├── fig1-4 (S1 pan-cancer figures)
│ │ └── coadread_mss/ (figS2a-e)
│ └── imvigor210/
│ ├── compute_tgjs_imvigor210.R # S3: IMvigor210 analysis
│ ├── data/ # S3 results matrix + summary
│ └── figures/ (figS3a-d)
├── runs/ # IRIS Gate Evo convergence runs
├── gold/ # Gold extractions from runs
├── data/
│ ├── vdac_modulators.csv # 17 VDAC-interacting compounds
│ └── vdac_isoform_comparison.csv
└── figures/ # Atlas overview figures
| File | Contents |
|---|---|
| S1 | Pan-cancer tGJS across 10,071 TCGA samples; boundary analysis; ENPP1 anti-correlation |
| S2 | COADREAD 4-stratum analysis; 20 markers x 4 strata; TREX1 co-occurrence finding; ENPP1 artifact correction |
| S3 | IMvigor210 null result; TMB interaction; immune phenotype stratification; OS analysis |
paper/vpa_cbd_hepatotoxicity_alert.md
Up to 30% of co-prescribed VPA + CBD patients develop ALT elevations >3x ULN. The standard CYP450 explanation is incomplete. VPA depletes mitochondrial reserves; CBD alters VDAC1 conductance. An estimated 2,000-3,500 US pediatric patients currently affected. Three testable steps to close the mechanistic gap.
| Commit | Description |
|---|---|
88ff1f7 |
S1 pan-cancer tGJS pipeline — 10,071 samples, null result |
af63c2b |
S2 COADREAD MSS stratified analysis — 5 Bonferroni hits |
af514d1 |
S2 writeup with synthesis sentence |
edb4880 |
S3 IMvigor210 analysis — second null |
61048d4 |
S3 writeup |
779f399 |
Manuscript restructured around S1-S2-S3 arc |
aeb2e44 |
Submission-ready docx with proper table formatting |
| Project | Link | Relationship |
|---|---|---|
| VDAC1 Gate-Opening Stack | templetwo/VDAC1-Gate-Opening-Therapeutic-Stack | Experimental architecture, bench protocols, GJS simulations |
| IRIS Gate Evo | templetwo/iris-gate-evo | Multi-model convergence engine |
| CBD Two-Pathway Model | templetwo/cbd-two-pathway-model | Origin of the gate-jamming question |
| IRIS Evo Findings | templetwo/iris-evo-findings | Run corpus and cross-run analysis |
| HuggingFace Dataset | TheTempleofTwo/vdac-pharmacology-atlas | Full convergence corpus |
| OSF Archive | osf.io/c9rqb | Preregistration and data archive |
@article{vasquez2026gatejamming,
title={Context-Specific Innate Immune Evasion via VDAC1 Gate-Jamming
in Microsatellite-Stable Colorectal Cancer},
author={Vasquez, Anthony J.},
year={2026},
doi={10.21203/rs.3.rs-8935902/v1},
url={https://doi.org/10.21203/rs.3.rs-8935902/v1},
journal={Research Square (Preprint)}
}CC BY 4.0. Use it, build on it, cite it.