Lung cancer is still the leading type of cancer worldwide and the primary cause of death for cancer patients (Siegel et al., 2020). The 5-year survival rate of lung cancer patients is only 17.8%, and more than half of them die within the first year after diagnosis (Zappa and Mousa, 2016). Small-cell lung cancer (SCLC) accounts for almost 15% of all lung cancer patients, and NSCLC is nearly 85%, with lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) being most prevalent (Zappa and Mousa, 2016). In 2015, it caused more than 2.8 million deaths in China, of which more than 40% were related to LUAD (Chen et al., 2016). The treatment of lung cancer has evolved significantly over the last decade. Recent studies have demonstrated that immunotherapy (especially immune checkpoint inhibitors (ICIs) (Wei et al., 2018) (Goodman et al., 2017), (Carlino et al., 2021) including programmed cell death protein 1/programmed cell death ligand 1 (PD-1/PD-L1) blockers) can improve survival in lung cancer patients. Immunotherapy stimulates anti-tumor immune responses in the immune system to fight tumors. Cancer immunotherapy aims to activate immune responses to remove cancer cells while leaving non-cancerous cells alone (Anagnostou and Brahmer, 2015). ICIs are now licensed for the treatment of a variety of malignancies (Cella et al., 2022) (Doki et al., 2022) (Kang et al., 2022). Several solid tumors, like lung cancer and melanoma, have had tremendous success (Robert et al., 2019). Whether as monotherapy or combination therapy, for patients with advanced NSCLC, ICIs constitute the gold standard of therapy. However, these medications are ineffective for certain patients, and only around one-third of patients react to ICIs. Although immune surveillance allows tumor cells to be identified, controlled, and killed, tumor cells avoid immune surveillance by decreasing immunogenicity and creating immunosuppressive networks (Zou, 2005) (Mohme et al., 2017) (Dersh et al., 2021). Therefore, it remains an unsolved challenge in cancer immunotherapy to transform these immunologically "cold" tumors into "hot" tumors reacting to ICIs.

Because apoptosis resistance is a universal feature of cancer, inducing non-apoptotic regulated cell death (RCD) is developing as a novel cancer therapeutic method. As a unique RCD, ferroptosis is distinct from apoptosis. Cancer cells susceptible to ferroptosis have metabolic characteristics that include high levels of polyunsaturated fatty acids (PUFA), overloaded iron stores, and a fragile glutathione peroxidase 4 (GPX4)-glutathione (GSH) defense system, and patients with these cancers may benefit better from treatments that target ferroptosis. According to research, certain intractable tumor cells are highly vulnerable to ferroptosis (Hangauer et al., 2017) (Tsoi et al., 2018). Traditional therapies, for example, promote apoptosis in cancer cells but are typically ineffective against mesenchymal cancer cells. These cancer cells are highly dependent on GPX4 to survive by detoxifying lipid peroxides due to the increased synthesis of phospholipids containing polyunsaturated fatty acid-containing phospholipids (PUFA-PLs), making them strongly sensitive to ferroptosis (Tsoi et al., 2018). It has been shown that ferroptosis is observed throughout peripheral immune tolerance (Xu et al., 2021a) (Kim et al., 2020) (Wu et al., 2021) (Forde et al., 2018) (Tang et al., 2020). Ferroptosis can both suppress tumor development and improve cancer cell immunotherapy through various signal pathways (Goodman et al., 2017) (Carlino et al., 2021). Therefore, for patients with immune-tolerant lung cancer, addressing ferroptosis may provide novel therapeutic options, and the combination of ferroptosis-targeted regulation with immunotherapy may be a focus of future study. In this paper, we systematically summarize the potential mechanism of ferroptosis inhibition in lung cancer, explore the role of ferroptosis in the tumor microenvironment (TME), and propose novel clinical options for lung cancer treatment.