Biliary Tract Cancers (BTC) are particularly difficult to treat since they are resistant to chemotherapy and immunotherapy. When used in conjunction with PD-L1 blocking, MEK inhibition (MEKi)-based regimens may prove effective in treating this condition. In advanced BTC patients, researchers hypothesize that combined inhibition of MEK and PD-L1 improves outcomes through modifying circulating soluble and cellular immune mediators. Blood samples from 77 patients with advanced BTC who were taking part in phase II clinical study of atezolizumab with or without cobimetinib were analyzed for immunological characteristics. Whole blood was separated into plasma and peripheral blood mononuclear cells (PBMC) to analyze soluble factors and immune cell populations. To determine which immunological markers are specific to BTC, the researchers compared baseline blood samples with those from healthy volunteers. High frequencies of CD8+BTLA+ T cells at baseline were associated with improved overall survival (OS), and platelet-derived growth factor B (PDGF-BB), placental growth factor (PlGF)-1, interleukin-5 (IL-5), and interleukin-17A (IL-17A) were all elevated in patients with BTC compared with healthy adult donors. Alterations in various parameters, including lower platelet-derived growth factor B (PDGF)-BB after combination treatment, were also found to correspond with increased overall and progression-free survival (PFS). To begin with, improved clinical outcomes were observed in patients whose IL23 and RANTES levels were higher. There was a negative correlation between overall survival (OS) and progression-free survival (PFS) in a study of patients treated with dual MEK/PD-L1 inhibition. Dual MEK/PD-L1 inhibition increased populations of CD4+TIM3+ and decreased CD8+VISTA+ T cells, correlating with worse OS and better PFS, respectively. These findings lend credence to the need for additional research into the synergistic effects of MEKi with immunotherapeutic strategies in improving clinical outcomes for individuals with advanced BTC.