Background: Accumulating evidence reveal complicated crosstalk amongst cancer-related fibroblasts (CAFs) and immune cells in tumor microenvironment (TME). However, interaction within CAFs and immune cells, and their relationship with clinical outcomes remain largely undetermined. Methods: Interaction between CAFs and immune cells was evaluated by the CD8+ T cells/CAFs ratio (CFR), denoting great difference within single-sample gene-set enrichment analysis (ssGSEA) scores. Association of CFR with survival was examined in TCGA/GEO lung cancer and TCGA pan-cancer cohorts. Correlation between CFR and immunotherapeutic efficacy was determined in five independent cohorts including melanoma, lung cancer and urothelial cancer. orrelations between CFR and objective response rates (ORR) reported in the literature following pembrolizumab monotherapy were calculated in 20 TCGA cancer cohorts. To translate the in silico findings into clinical use, immunohistochemically-detected CD8/α-SMA ratio was used as prognostic and immuno-therapeutically predictive biomarker in two lung cancer cohorts. Furthermore, correlation within CFR, TMB, PD-L1, and molecular/genomic characteristics of CFR subgroups was also evaluated. Results: A moderately positive correlation existed between CAFs and immune cells infiltration in various cancer types. Higher immune cells/CAFs ratios indicated favorable prognosis regardless of distinct immune cells. Higher CFR, an independent risk factor and complementary factor to PD-L1 and TMB, was strongly associated with improved survival in melanoma, lung cancer and urothelial cancer immunotherapy cohorts (log-rank test, P< 0.05). Moreover, CFR averages across cancer types provided a higher correlation coefficient with the ORR following pembrolizumab monotherapy when compared to PD-L1 expression and TMB, r = 0.65 versus 0.36 and 0.31, respectively. Finally, in the clinical setting, CD8/α-SMA ratio was validated as an independent prognostic and predictive biomarker of immunotherapy efficacy in non-small cell lung cancer (HR, 0.21, 95% CI, 0.12-0.37, P< 0.001; HR, 0.37; 95% CI, 0.19-0.75; P< 0.001). Low CFR was associated with upregulation of hypoxia, TGF-β signaling, epithelial-mesenchymal transition and angiogenesis. Conclusions: CFR was a promising biomarker in the prediction of immunotherapeutic efficacy across various malignancies.