Omega-3 PUFAs Synergize with Anti-PD-1 Therapy to Counter Cholesterol-Driven NSCLC Immune Evasion

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer mortality, frequently characterized by poor response rates to immune checkpoint inhibitors (ICIs). A growing body of evidence implicates nutritional factors and altered tumor metabolism as key drivers of both progression and immunotherapy resistance. Specifically, cholesterol is known to fuel tumor growth and facilitate immune evasion by accumulating in the tumor microenvironment (TME). Conversely, ω-3 polyunsaturated fatty acids (PUFAs) possess anti-inflammatory and immunostimulatory effects.

The paper, "Dietary ω-3 polyunsaturated fatty acids (PUFAs) reduce cholesterol-driven non-small cell lung cancer (NSCLC) progression in mouse models of disease," meticulously dissects this metabolic dichotomy. The authors reveal that a high-cholesterol diet accelerates NSCLC progression via EMT and immunosuppressive cytokine cascades, while ω-3 PUFA supplementation effectively reverses these pathways and synergistically augments the efficacy of PD-1 blockade.

Cholesterol: A Pro-Tumoral Metabolic Switch and Immune Evasion Driver

The study confirmed the potent pro-tumoral role of cholesterol metabolism in both human patients and murine models. Clinically, elevated serum triglycerides correlated with poor outcomes in NSCLC patients. Mechanistically, tumor tissue analysis showed a dysfunctional metabolic pathway: increased intracellular cholesterol accumulation (via ACAT1) and reduced efflux (ABCA1 downregulation) fuels the production of the pro-tumoral metabolite, 27-hydroxycholesterol (27-HC), indicated by high CYP27A1 and low CYP7B1 expression. This accumulation drives proliferation and metastatic potential through the activation of signaling pathways involving NFkB p65, AKT, PPIB, and the Epithelial-Mesenchymal Transition (EMT) markers SNAIL and Vimentin. Consistent with this, mice fed a high-cholesterol diet (AD) displayed significantly increased tumor load and elevated pro-tumoral and immunosuppressive cytokines (IL-6, IL-10, IL-17A) in the TME.

ω-3 PUFAs: An Immune System Reprogrammer and Cytotoxic Enhancer

Dietary ω-3 PUFA supplementation (OD/ID diets) demonstrated a powerful counter-effect against these cholesterol-driven pathways. Supplementation was shown to reduce tumor burden and simultaneously reverse metabolic dysregulation by lowering the expression of cholesterol accumulation enzymes (HMGCR, ACAT1) and downstream EMT mediators (AKT, NFkB p65, PPIB). Crucially, ω-3 PUFAs mitigated immunosuppression by reducing the secretion of suppressive cytokines like IL-10 and decreasing the infiltration of immune-suppressive cells, specifically CCR4+ Regulatory T cells (Tregs). This shift resulted in an enhanced anti-tumoral immune response, evidenced by increased ex vivo cytotoxicity of lung cell supernatants and a notable boost in NK cell frequency and activity (higher NKG2D expression) in the lung.

Synergy with Checkpoint Blockade: Contribution of ichorbio

The most critical finding was the powerful, synergistic cooperation between ω-3 PUFA nutrition and modern immunotherapy. The authors utilized the Anti-PD-1 antibody (ichorbio, ICH1132, RRID: AB_2921498) to test combination therapy in the murine BALB/c L1C2 model. The ω-3 PUFA diet combined with anti-PD-1 therapy (ICH1132) synergistically suppressed tumor growth and drove the most potent anti-tumor immune phenotype. This combination resulted in the highest levels of activated NK cells and, crucially, a significant reduction in splenic monocytic Myeloid-Derived Suppressor Cells (MDSCs) (Ly6G– Ly6Chigh), a cell population highly linked to ICI resistance. The use of this specific ichorbio reagent provided the essential in vivo tool to confirm that dietary modulation is a viable complementary strategy to directly augment the therapeutic efficacy of checkpoint inhibitors.

Implications and Future Directions

This study establishes a strong preclinical foundation for nutritional immunology, showing that simple, targeted dietary changes can sensitize tumors to ICIs by simultaneously reversing metabolic-driven progression and bolstering cytotoxic immunity.

Implications for the Field 

The work provides a direct molecular link between metabolic dysregulation (cholesterol/27-HC) and immune evasion (MDSCs/Tregs), proposing a low-toxicity, rational strategy to improve ICI response rates in NSCLC. The synergistic findings urgently support the initiation of clinical trials investigating defined ω-3 PUFA supplementation as an adjunct to standard ICI regimens.

Proposed Future Experiments

To accelerate clinical translation, three lines of inquiry are crucial:

1. Specific ω-3 Mechanistic Dissection: Future work must isolate the effects of the specific long-chain ω-3 PUFAs (EPA and DHA) to determine the optimal agent for MDSC suppression and NK cell activation, necessary for developing a pharmacologically optimized supplement.

2. Targeting TME Macrophages: Since 27-HC promotes M2 macrophage polarization, an essential follow-up is to quantify if ω-3 PUFAs directly influence macrophage polarization (e.g., shifting them from M2 to M1) to detoxify the TME of pro-angiogenic factors and inflammatory cytokines.

3. Optimal Dosing and Timing: A time-course analysis is needed to determine the optimal pre-treatment dose and duration of ω-3 PUFA intervention required to maximally sensitize the immune system prior to and during PD-1 blockade.

Reference

Harre, P., Hohenberger, K., Krammer, S. et al. Dietary ω−3 polyunsaturated fatty acids (PUFAs) reduce cholesterol-driven non-small cell lung cancer (NSCLC) progression in mouse models of disease. Commun Med 5, 432 (2025). https://doi.org/10.1038/s43856-025-01193-y