Single-Cell Atlas of Pan-Cancer Immunotherapy Reveals the Role of Ferroptosis in Exhausted Macrophages and Immune Therapy Resistance

SLC40A1 (also known as ferroportin) is a key iron exporter that maintains intracellular iron homeostasis and regulates macrophage function. In this study, we found that a metabolically reprogrammed SLC40A1+ subset of tumor-associated macrophages (TAMs), characterized by ferroptosis resistance and immunosuppressive features, is enriched in patients who do not respond to PD-1 immune checkpoint blockade therapy. To further investigate the regulatory role of SLC40A1 in macrophage immune function and ferroptosis resistance, we performed RNA sequencing on differentiated THP-1 macrophages transfected with either SLC40A1-targeting siRNA or negative control siRNA. RNA-seq of THP-1-derived macrophages transfected with si-SLC40A1-1, si-SLC40A1-2, or negative control siRNA following PMA-induced differentiation.