Distinct molecular and tumor microenvironment characteristics of mucinous adenocarcinoma in colorectal cancer

Summary Mucinous colorectal adenocarcinoma (MAC) is characterized by poor prognosis and therapy resistance, yet its molecular and tumor microenvironment (TME) features remain inadequately understood, limiting the identification of effective therapeutic targets. Here, we performed a comprehensive analysis of MAC tumor characteristics and the TME using large-scale genetic and transcriptomic sequencing datasets. Our findings reveal that MAC tumor cells harbor a higher frequency of canonical mutations yet exhibit lower chromosomal instability. Additionally, we observed an increased infiltration of natural killer (NK) cells and SPP1 highly expressed macrophages (Mac-SPP1) within the TME, along with heightened fibroblastic and myeloid inflammatory signals. Mac-SPP1, characterized by M2 macrophages, was associated with poor prognosis. Furthermore, we identified key prognosis-related genes, including FSCN1, SLC11A1, and PLXND1, and proposed potential therapeutic agents for overcoming treatment resistance. Our findings offer valuable insights into the molecular mechanisms underlying MAC and highlight the critical need for novel therapeutic strategies.