Abstract Background: Admixture of archaic (Neandertal and Denisova) and ancestral genes enhanced natural immunity during out of Africa migrations and modulates modern susceptibility to autoimmunity and cancer. We investigated a series of functional interactions between archaic and ancestral STING1 and TLR genes to identify vulnerabilities that could be addressed by STING agonist therapy. Methods: Gene variants from 10,389 cancer patients (pts) were obtained from TCGA. Archaic sequences were accessed using UCSD genome browser 410. Linkage disequilibrium was investigated using LDlink v5.0. Patient 1 was treated within NCT04144140. Results: STING1 variants were overrepresented in gastroesophageal cancer pts. V48V (rs7447927-C>G) with GWAS of lower rate of Asian esophageal cancer was in linkage disequilibrium with the reference alleles of the partially active HAQ and REF variants, and with rs13153461, present in Neandertal sequences. STING1 rs7447927-G was also associated with HLA A*24:02 (p<0.001), A*02:06 (p=0.01), and A*31:01 (p=0.02), of Neandertal origin. We then investigated a potential epistasis between STING1 rs7447927-G and TLR variants associated with decreased H. pylori prevalence: Neandertal-like TLR10 I775V (rs4129009) and ancestral TLR6 S249P (rs5743810). No independent prognosis was identified in 32 TCGA legacy studies; however, in upper aerodigestive (oral cavity, oropharynx, esophageal, gastric, biliary tract) tumor pts who carried reference/heterozygous TLR6 S249P and/or reference TLR10 I775, Neandertal-associated STING1 rs7447927-G zygosity was a strong predictor of survival. Hazards ratio for rs7447927-GG vs GC (4.8 vs 2.7 yrs. median survival), and GG vs CC (4.8 vs 1.8 yrs.) were respectively 0.71 and 0.53, N=713, p=0.0003. Patient 1 was a 75 yr.-old male esophageal cancer pt with GERD, Barrett’s esophagus and TLR6 S249/STING1 rs7447927-GC, who was progressing from anti-PD1 and chemotherapy and received 75 microg intra-tumoral injections of the STING agonist E7766. Non treatment-related grade 2 events of anemia and hyponatremia, serum IFNbeta and IP10 levels induction, 20% tumor size reduction including abscopal effects, and 6.3 months PFS benefit were observed. Conclusion: Genotyping of STING1, TLR6-10 variants could contribute to identify pts who may benefit from E7766 treatment. Citation Format: Antonio Gualberto, Tenghui Chen, Catherine Scholz, Jason Luke. Neandertal introgressions contribute to upper aero-digestive tract tumor patient survival and identify patients who may benefit from STING agonist treatment [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P110.