Intratumor APOL3 delineates a distinctive immunogenic ferroptosis subset with prognosis prediction in colorectal cancer

With the essential role of lipid transporting signaling in cancer‐related immunity, apolipoprotein L3 (APOL3), a member of the apolipoprotein L gene family, demonstrated significant modulation ability in immunity. However, the expression profile and critical role of APOL3 in colorectal cancer (CRC) remain unclear. This study aimed to investigate the prognostic significance of APOL3 expression and its biological predictive value in CRC. The study enrolled multiple cohorts, consisting of 911 tumor microarray specimens of CRC patients from Zhongshan Hospital, 412 transcriptional data from The Cancer Genome Atlas, and 30 single‐cell RNA sequencing (scRNA‐seq) from internal and external CRC patients. APOL3 mRNA expression was directly acquired from public datasets, and APOL3 protein expression was detected using immunohistochemistry. Finally, the associations of APOL3 expression with clinical outcomes, immune context, and genomic and ferroptotic features were analyzed. Low APOL3 expression predicted poor prognosis and inferior responsiveness to 5‐fluorouracil‐based adjuvant chemotherapy (ACT) and targeted therapy. APOL3 fosters an immune‐active microenvironment characterized by the promotion of ferroptosis, downregulation of macrophages, and upregulation of CD8+ T cell infiltration. Moreover, the expression of APOL3 in CD8+ T cells is intrinsically linked to ferroptosis and immune activation in CRC. In summary, APOL3 serves as an independent prognosticator and predictive biomarker for immunogenic ferroptosis, ACT, and targeted therapy in CRC. Furthermore, the APOL3 signaling activator could be a novel agent alone or in combination with current therapeutic strategies for CRC. Our study demonstrated that apolipoprotein L3 (APOL3) is a protective independent prognosticator and yields better responsiveness to both adjuvant chemotherapy (ACT) and targeted therapy in colorectal cancer (CRC). Furthermore, intratumoral APOL3 fostered an immune‐activated tumor microenvironment (TME) and was associated with certain features of ferroptosis. Moreover, APOL3 signaling may be applied alone or as a complementary therapy to reinvigorate ACT and targeted therapy in CRC.