Mitochondrial fitness in circulating T cells predicts neoadjuvant therapy response in locally advanced colorectal cancer.

Background: Traditional immunophenotyping based on cell counts has limited value in predicting neoadjuvant treatment outcomes for locally advanced colorectal cancer (LACRC). Because mitochondrial fitness is an essential factor in T-cell function, we hypothesized that the pretreatment metabolic profile of circulating T cells could predict therapeutic response. This study aimed to develop a novel pretreatment assessment system based on peripheral blood immunometabolic parameters. Methods: Baseline peripheral blood samples were prospectively collected from 72 patients with LACRC enrolled in the OPTICAL2 phase II clinical trial (NCT05571644), which compared neoadjuvant mFOLFOXIRI plus cadonilimab versus mFOLFOXIRI or mFOLFOX6. Multicolor flow cytometry was used to analyze the immunophenotype and mitochondrial characteristics of circulating T-cell subsets. A composite index, named Tscore, was constructed by using multivariate logistic regression. This model integrated five parameters: the CD4/CD8 ratio, mitochondrial mass of CD4⁺ and CD8⁺ central memory T cells and those of effector memory T cells. Results: Patients achieving pathological complete response showed higher T-cell mitochondrial mass and lower levels of low membrane potential than non-responders. The baseline Tscore predicted pathological complete response (pCR) with an area under the curve (AUC) of 0.976 (95% CI, 0.927-1.000; Conclusions: Tscore is a noninvasive biomarker for predicting neoadjuvant therapy response in LACRC. These findings highlight the importance of pretreatment T-cell metabolic characteristics and provide a potential tool for individualized response assessment.