CPT1A is indispensable for tumor progression and LCSCs maintenance in lung cancer. a–c Relevance of CPT1A expression with the tumor progression in NSCLC patients. Representative IHC staining for CPT1A in the normal or cancerous lung tissues from NSCLC patients (left) and IHC score of CPT1A were depicted on the right. Scale bars, 500 μm (up); 50 μm (down) (insets) (a). Correlation of CPT1A level with the clinical stages of NSCLC patients (b) and overall survival (OS) of NSCLC patients with lung cancer stratified according to the expression of CPT1A in the tumor (c). d–i Effects of Cpt1a on tumor progression in the transgenic mouse. Construction strategy for the transgenic SKC (Sftpc-CreERT2; KrasG12D; Cpt1aflox/flox) mice and the experimental scheme (d). Representative micro-CT image (left) and H&E staining (right) of the lung tissue from SKC or control mice. Scale bars, 2 mm (micro-CT); 1 mm (H&E, left); 5 mm (H&E, right) (insets) (e). Overall survival of SKC or control mice (f). Percentages of distinct types of immune cells (g) and IFNγ cells gated on CD45 cells in the lung tissues from SKC or control mice (h). Representative images of C11-BODIPY staining in the lung tissue from SKC or control mice. Scale bars, 50 μm (insets) (i). j Spare respiratory capacity in adherent or spheroid cells of LLC-shNC/shCPT1A cells measured by using Seahorse XF Pro analyzer with mitochondrial stress test. Data represent the mean ± s.d.; n = 3-6 samples. k Representative tumor-sphere images of H1299-shNC/shCPT1A cells cultured with sphere-forming medium. Scale bars, 200 μm (insets)；zoomed images (left bottom, 2.5 times amplification). l Percentages of ALDH cells in H1299-shNC/shCPT1A cells determined by flow cytometry. m, Representative western blot for CPT1A, SOX2, OCT4 and NANOG in adherent, spheroid or shNC/shCPT1A cells of H1299 cells. *P < 0.05, **P < 0.01, ***P < 0.001; ns: not significant. The statistical analysis was performed using a two-tailed Student’s t-test or Pearson’s correlation test+++. credit:doi: 10.1038/s41392-024-01772-w

Lung cancer remains one of the most common causes of cancer-related deaths worldwide. Despite significant advancements in immunotherapy, the five-year survival rate for lung cancer patients is still around 16%, highlighting the urgent need to explore new therapeutic targets. Research indicates that cancer stem cells (CSCs) play a crucial role in tumor immune evasion and resistance to immunotherapy. Importantly, ferroptosis is closely associated with the regulation of energy metabolism in CSCs, suggesting a potential therapeutic avenue to target these resilient cells. Ferroptosis is a form of cell death driven by iron-dependent lipid peroxidation, and it serves as a foundational concept in understanding the vulnerability of lung cancer cells to new therapeutic approaches. By manipulating this cell death pathway, researchers have proposed a novel method to enhance the sensitivity of tumors to immunotherapeutic drugs. This approach aims to exploit the unique metabolic vulnerabilities of cancer cells, potentially overcoming some of the resistance mechanisms that diminish the efficacy of existing treatments.

Lei and colleagues developed a transgenic mouse model with a lung-specific knockout of CPT1A, referred to as SKC mice. Their findings demonstrated a significant reduction in tumor burden and an extension in survival among CPT1A-deficient mice compared to controls. This was paralleled by enhanced CD8+ T cell infiltration and activation within the tumor microenvironment, suggesting that the absence of CPT1A could potentiate the immunogenicity of ferroptosis. Utilizing specific small molecule inhibitors, like etomoxir (ETO), Lei's team targeted CPT1A in the H1299 lung cancer cell line. The treatment led to an increased sensitivity to ferroptosis, evidenced by heightened levels of lipid peroxidation products and changes in mitochondrial morphology. These cellular alterations were crucial in delineating the role of CPT1A in modulating the oxidative stress response, particularly through the NRF2/GPX4 signaling pathway, enhancing the cells' antioxidant capacity and influencing their susceptibility to cell death. The study's implications are profound, aligning with other research that emphasizes the interplay between metabolic pathways and immune response. Carlo et al.'s review further corroborates the idea that enhancing ferroptosis can increase the immunogenicity of cancer cells, making them more susceptible to T-cell mediated destruction. Additionally, the identification of the CPT1A/c-Myc positive feedback loop provides a new avenue for disrupting the metabolic comfort zone of cancer cells, offering a dual approach to therapy by directly targeting tumor growth and facilitating immune system access.

Indeed, while the paper provides valuable scientific insights and methodologies, it calls for further in-depth research and validation in multiple aspects. One important question is whether there are other molecules simultaneously affected by these inhibitors, which could lead to unforeseen effects or off-target impacts. Additionally, the effectiveness of ferroptosis induction and CPT1A inhibition may vary across different stages of tumor development (such as early versus late stages), raising the question of how treatment strategies could be adjusted to accommodate the evolving nature of tumors. Moreover, while animal experiments and in vitro cell studies offer valuable insights, the real challenge lies in validating these findings through clinical trials to establish their efficacy and safety in humans. This step is crucial for advancing toward clinical application. By addressing these doubts and challenges, the potential of CPT1A and ferroptosis in lung cancer treatment can be better harnessed, offering more effective treatment options for patients. This entails a comprehensive approach that includes robust preclinical validation, thoughtful clinical trial design, and continuous monitoring of treatment outcomes to ensure that the therapeutic benefits are maximized while minimizing potential risks.

Future research should focus on validating these findings in clinical trials, assessing the long-term safety and efficacy of CPT1A inhibitors, and exploring the combination of these agents with existing immunotherapies.

Conclusion

The research by Lei and colleagues opens new pathways for the treatment of lung cancer by integrating the induction of ferroptosis with immunotherapy strategies. This approach may represent a significant shift in how we treat lung cancer, highlighting the importance of targeting metabolic pathways to combat this devastating disease. As we continue to unravel the complex interactions between cell death pathways and the immune system, targeting CPT1A stands out as a promising strategy in the evolving landscape of cancer therapy.

Reference：

1.Ma L, Chen C, Zhao C, Li T, Ma L, Jiang J, Duan Z, Si Q, Chuang TH, Xiang R, Luo Y. Targeting carnitine palmitoyl transferase 1A (CPT1A) induces ferroptosis and synergizes with immunotherapy in lung cancer. Signal Transduct Target Ther. 2024 Mar 7;9(1):64.

2.Genova C, Dellepiane C, Carrega P, Sommariva S, Ferlazzo G, Pronzato P, Gangemi R, Filaci G, Coco S, Croce M. Therapeutic Implications of Tumor Microenvironment in Lung Cancer: Focus on Immune Checkpoint Blockade. Front Immunol. 2022 Jan 7;12:799455.