TNFRSF18+ Tregs Impair Immunotherapy Efficacy in Immunosuppressed Colon Cancer Patients

Immunotherapy shows limited effectiveness in immunosuppressed colon cancer (CC), highlighting the need for a reliable biomarker to identify eligible patients. In this study, we characterized patient immunophenotypes as Immunity-High and Immunity-Low using ssGSEA scores from the TCGA-COAD database, revealing high expression of survival-inhibiting markers in the Immunity-Low group. Single-cell analysis localized these markers, which were validated through immunofluorescence and survival analyses in an immunotherapy cohort. Our findings indicate that the immunophenotype effectively differentiates patient groups with distinct immune cell infiltration patterns and significant survival differences (p = 0.038). Notably, elevated TNFRSF18 expression in the Immunity-Low group was linked to poorer prognosis (p = 0.030), with predominant expression found in Tregs. Increased TNFRSF18 ⁺ Treg infiltration correlated with shorter disease-free and overall survival post-immunotherapy (p = 0.041 and p = 0.007, respectively). Additionally, TNFRSF18-low organoids were responsive to anti-PD-1 treatment, unlike TNFRSF18-high organoids. This study is the first to identify TNFRSF18 ⁺ Tregs as prognostic markers and predictors of immunotherapy response in immunosuppressed CC, suggesting that TNFRSF18 agonists could enhance anti-PD-1 therapy in these patients.