Metabolic Reprogramming of Tumor-Associated Macrophages via the GM-CSF–PPARγ Axis Supports EGFR-Mutant Lung Adenocarcinoma Progression: Therapeutic Implications


Lung cancer, particularly lung adenocarcinoma (LUAD), represents a significant challenge in oncology due to its high mortality rates and the limited efficacy of current treatments, including targeted therapies and immunotherapies.  A new study published in Cancer Discovery and led by Professors Christian Metallo and Susan Kaech from the  Salk Institute for Biological Studies in California, the authors highlighted the molecular heterogeneity of LUAD, underscored by prevalent mutations in KRAS, EGFR, and ALK, which, despite initial responses to targeted therapies, often lead to resistance. This resistance is particularly notable in EGFR-mutant LUADs, which also show poor responsiveness to immune-checkpoint blockade (ICB), underscoring the complexity of the tumor microenvironment and the cancer-immunity interplay in LUAD.

The authors focused in their study on the tumor microenvironment, particularly the role of tumor-associated macrophages (TAMs) and their plasticity, which can either support or hinder tumor progression. The researchers provide compelling evidence that TAMs, through their metabolic and immunologic functions, are crucial in the progression of LUAD. They demonstrate how LUAD cells exploit TAMs for metabolic support, specifically through the GM-CSF–PPARγ signaling axis, to facilitate tumor growth. This interaction not only underscores the metabolic flexibility of cancer cells but also highlights potential therapeutic targets within the tumor microenvironment. The researchers used flow cytometry, immunofluorescence, and single-cell RNA sequencing (scRNA-seq) to profile immune cells within LUAD tumors, focusing on TAMs’ phenotypes and functions. TAMs in LUAD were found to exhibit a tolerogenic and pro-tumorigenic phenotype, characterized by high expression of PD-L1 and CD200R, reduced secretion of pro-inflammatory cytokines, and an overall immunosuppressive profile. This was in stark contrast to TAMs from non-tumorigenic lung tissue, highlighting the role of the tumor microenvironment in TAM polarization.

Using genetically modified mouse models and pharmacological inhibition, the researchers explored the impact of blocking PPARγ or GM-CSF signaling on TAM function and tumor growth. They employed mice with lung-specific expression of oncogenic EGFR mutations, enabling the study of EGFR-driven LUAD. Inhibiting PPARγ or GM-CSF signaling disrupted the metabolic programming of TAMs, notably affecting lipid metabolism and cholesterol efflux mechanisms. This alteration was associated with reduced tumor growth and a shift towards a more inflammatory TAM phenotype, indicating that EGFR-driven LUAD exploits TAMs’ metabolic functions for tumor progression. The team conducted lipid tracing studies using labeled fatty acids and cholesterol, combined with co-culture systems of TAMs and LUAD cells, to track the transfer of lipids from TAMs to cancer cells. TAMs were found to supply LUAD cells with essential lipids, particularly cholesterol, via efflux mechanisms regulated by the GM-CSF–PPARγ axis. This metabolic support facilitated oncogenic signaling in LUAD cells, notably EGFR phosphorylation, underscoring a novel mechanism of tumor progression. Researchers utilized therapeutic interventions targeting TAM metabolism, including PPARγ antagonists and statin treatment, to evaluate the impact on LUAD progression in their mouse models. Pharmacologically targeting TAM metabolism significantly impaired LUAD growth, highlighting the therapeutic potential of disrupting the metabolic support TAMs provide to tumor cells. Moreover, the combination of statin treatment with PPARγ inhibition synergistically reduced tumor growth, suggesting a novel combinatorial therapeutic strategy.

The series of experiments conducted by Metallo, Kaech, and their team have elucidated a critical role for TAMs in supporting LUAD progression through metabolic mechanisms, particularly lipid metabolism and cholesterol efflux. Their findings offer novel insights into the tumor microenvironment’s contribution to cancer progression and therapy resistance. Importantly, the study identifies new therapeutic targets within the metabolic and immunological functions of TAMs, offering promising strategies for improving outcomes in LUAD patients. This work significantly advances our understanding of the complex interactions between cancer cells and the immune system, paving the way for innovative treatments that could have a profound impact on lung cancer therapy.  The study meticulously demonstrates that blocking PPARγ in TAMs or inhibiting the GM-CSF–PPARγ axis can significantly impair tumor progression by disrupting the metabolic symbiosis between TAMs and LUAD cells. This disruption leads to an increased antitumor immune response, suggesting a novel therapeutic avenue that combines metabolic targeting of TAMs with conventional therapies to overcome resistance in LUAD. Moreover, the research sheds light on the significance of lipid metabolism in cancer progression, with a particular focus on cholesterol efflux mechanisms mediated by TAMs. By elucidating the molecular pathways involved in this process, the study not only enhances our understanding of cancer metabolism but also identifies metabolic vulnerabilities that could be exploited for therapeutic gain. The finding that TAMs can modulate EGFR signaling in LUAD cells through metabolic means adds an important layer to our understanding of cancer biology and opens new avenues for research and therapy. In conclusion, the work of Metallo, Kaech, and their team represents a pivotal step forward in our understanding of LUAD biology and the complex interplay between cancer cells and the immune system. Their findings underscore the potential of targeting the metabolic and immunological functions of TAMs as a promising strategy to improve outcomes for patients with LUAD.

Metabolic Reprogramming of Tumor-Associated Macrophages via the GM-CSF–PPARγ Axis Supports EGFR-Mutant Lung Adenocarcinoma Progression: Therapeutic Implications - Medicine Innovates

About the author

Susan Kaech, PhD
Professor and Director
NOMIS Center for Immunobiology and Microbial Pathogenesis
Salk Institute
La Jolla, California

Susan M. Kaech, PhD, is a Professor, Director of the NOMIS Center for Immunobiology and Microbial Pathogenesis, and holder of the NOMIS Chair at the Salk Institute for Biological Studies.

Dr. Kaech aims to understand how memory T cells are produced during infection and vaccination, how they function, and why in some particular cases, they fail to induce long-term immunity. Her lab has been a leader in using genetic and molecular tools to identify the genes and signaling molecules involved in generating two specific types of memory T cells, CD4 and CD8, from precursor cells during both acute and chronic viral infections. She and her team discovered more than half a dozen important regulatory genes, as well as several types of key molecules called cytokines, which influence memory T cell development.

About the author

Professor Christian Metallo
Molecular and Cell Biology Laboratory
Salk Institute

The Metallo laboratory at the Salk Institute for Biological Studies applies a multi-disciplinary approach to understand how metabolism drives disease states and uses this information to improve people’s health and wellness. We incorporate analytical chemistry, mass spectrometry, cell biology, and systems-based modeling to study metabolic regulation in cells, tissues, animals, and people. We integrate the use of stable isotope tracers and engineering principles to quantitatively describe how metabolic function (or dysfunction) contributes to human disease.


Kuhlmann-Hogan A, Cordes T, Xu Z, Kuna RS, Traina KA, Robles-Oteíza C, Ayeni D, Kwong EM, Levy S, Globig AM, Nobari MM, Cheng GZ, Leibel SL, Homer RJ, Shaw RJ, Metallo CM, Politi K, Kaech SM. EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth. Cancer Discov. 2024 Jan 25:OF1-OF22. doi: 10.1158/2159-8290.CD-23-0434.

Go To Cancer Discov.