Emerging roles of IL4I1 in regulating tumor immunity and ferroptosis

The tumor microenvironment (TME) plays a crucial role in driving tumor progression and facilitating immune evasion, acting as a complex network in which immune cells, stromal components, and tumor cells interact dynamically. Among the various factors influencing the TME, interleukin-4-induced protein 1 (IL4I1) has emerged as a key regulator of immune suppression and tumor growth. Through its enzymatic activity, IL4I1 metabolizes aromatic amino acids into a plethora of bioactive metabolites that inhibit ferroptosis and activate the aryl hydrocarbon receptor (AHR) signaling, thereby promoting anti-inflammatory macrophage polarization, regulatory T cell differentiation, and inhibition of effector T lymphocytes, ultimately inducing immune tolerance. These processes facilitate immune escape of cancer cells within the TME, where IL4I1 expression is often elevated and associated with poor prognosis. This review highlights the multifaceted role of IL4I1 within the TME, focusing on its immune regulatory function and anti-ferroptotic function. By exploring IL4I1's function in regulating different immune cell subsets and new role in promoting tumor resistance to ferroptosis, we discuss the major unanswered questions about how IL4I1 regulates tumor immunity, and propose the significance of developing targeted therapies that inhibit IL4I1, potentially in combination with inhibitors targeting IDO1 or immune checkpoints, to enhance antitumor immunity and improve clinical outcomes of cancer patients.