Worldwide, lung cancer leads in cancer-related deaths, with non-small cell lung cancer (NSCLC) comprising approximately 85% of the cases [1]. Extensive clinical evidence and epidemiological studies have demonstrated that chronic obstructive pulmonary disease (COPD) is a recognized independent risk factor for NSCLC [2]. Patients with NSCLC complicated by COPD not only have poorer outcomes but also exhibit unique pathological characteristics in their tumor microenvironment [3]. The long-term, chronic inflammatory state driven by COPD is considered a key factor in shaping this pro-tumor microenvironment, as it remodels the function of immune cells, ultimately leading to a significant impairment of the body's anti-tumor capacity [4].

In the complex tumor immune response, CD4+ helper T cells play a central regulatory role, and their functional integrity is the foundation of effective antitumor immunity [5]. However, in NSCLC, especially in the microenvironment of COPD, persistent inflammatory factor stimulation and tumor antigen exposure often induce CD4+ T cells to enter a state of functional exhaustion [6]. This state is characterized by impaired proliferative capacity and dysregulated cytokine secretion, making it one of the key mechanisms enabling tumor immune escape [7]. Therefore, elucidating the molecular networks driving CD4+ T cell dysfunction in the specific pathological context of COPD-associated NSCLC is of critical importance for developing more effective immunotherapy strategies.

Recent research advances have closely linked cellular metabolism and programmed cell death mechanisms to T cell function [8]. Ferroptosis, an iron-dependent, lipid peroxidation-marked non-apoptotic form of cell death, has been shown to play a key role in tumor immunity [9]. Studies suggest that inducing ferroptosis in T cells may represent a novel strategy for tumors to evade immune surveillance [10], [11]. However, The question of whether specific upstream molecular pathways exist in the chronic inflammatory microenvironment related to COPD that alter the ferroptosis sensitivity of CD4+ T cells and affect antitumor immunity requires more research. In this context, RNA-binding proteins (RBPs), as key executors of post-transcriptional regulation, offer a highly promising research direction due to their ability to rapidly integrate environmental signals and finely regulate target gene expression [12].

Despite this research background, direct evidence linking specific RBPs to T cell ferroptosis remains scarce. Aly/REF output factor (ALYREF) is a multifunctional RBP whose classical role in mRNA processing and export has been extensively reported [13], [14]. Recent research has further demonstrated that ALYREF contributes to non-small cell lung cancer progression through transcriptional or post-transcriptional regulation within tumor cells, providing important insights into its tumor cell–intrinsic functions [15]. However, whether ALYREF plays a role in immune regulation, particularly in shaping CD4+ T cell metabolic fitness and susceptibility to ferroptosis within the tumor microenvironment, remains largely unexplored. On the other hand, ZW10-interacting protein (ZWINT) has long been considered a component of the kinetochore complex that ensures precise chromosome separation [16]. Notably, aberrant upregulation of ZWINT has been reported in multiple tumor types, including NSCLC, and is associated with poor clinical outcomes [17], suggesting potential non-canonical functions beyond mitosis. Importantly, the expression pattern of ZWINT in immune cells, its regulatory mechanisms, and its potential impact on T cell function and fate remain unclear.

Aiming to fill existing research gaps, this study intends to uncover a new mechanism that links post-transcriptional regulation to T cell ferroptosis. We propose a core hypothesis: in the microenvironment of COPD-associated NSCLC, ALYREF directly binds to and enhances the stability of ZWINT mRNA, thereby upregulating ZWINT protein expression in CD4+ T cells. The abnormal accumulation of ZWINT protein, as a key downstream effector molecule, induces mitochondrial dysfunction and ultimately triggers ferroptosis in CD4+ T cells. We hypothesize that this cell event mediated by the ALYREF-ZWINT axis is a key link in the immune suppression and tumor progression. This study validated the function of this regulatory axis through systematic in vitro and in vivo experiments, with the aim of providing new insights into the immune escape mechanisms of COPD-associated NSCLC and identifying potential molecular targets for clinical intervention.