Targeting neoadjuvant chemotherapy-induced metabolic reprogramming in pancreatic cancer promotes anti-tumor immunity and chemo-response

The molecular dynamics of pancreatic ductal adenocarcinoma (PDAC) under chemotherapy remain incompletely understood. The widespread use of neoadjuvant chemotherapy (NAC) provides a unique opportunity to investigate PDAC samples post-chemotherapy. Leveraging a cohort from Fudan University Shanghai Cancer Center, encompassing PDAC samples with and without exposure to neoadjuvant albumin-bound paclitaxel and gemcitabine (AG), we have compiled data from single-cell and spatial transcriptomes, proteomes, bulk transcriptomes, and metabolomes, deepening our comprehension of the molecular changes in PDACs in response to chemotherapy. Metabolic flux analysis reveals that NAC induces a reprogramming of PDAC metabolic patterns and enhances immunogenicity. Notably, NAC leads to the downregulation of glycolysis and the upregulation of CD36. Tissue microarray analysis demonstrates that high CD36 expression is linked to poorer survival in patients receiving postoperative AG. Targeting CD36 synergistically improves the PDAC response to AG both in vitro and in vivo, including patient-derived preclinical models. [Display omitted] •The proteo-transcriptomic differences in chemo-treated and untreated PDAC are shown•Analyzing immune and metabolic changes tied to chemotherapy in PDAC•Boosting the potency of chemotherapy via CD36 targeting, with translational potential Tang et al. conduct a comprehensive multi-modal analysis, uncovering that neoadjuvant chemotherapy has a profound impact on the immune microenvironment and metabolic patterns in pancreatic ductal adenocarcinoma. Their findings suggest that targeting CD36 could potentially enhance the effectiveness of chemotherapy and bolster the anti-tumor immune response.