SUMMARY: Immune checkpoint inhibitors (ICIs) have dramatically transformed treatment landscape across multiple malignancies, producing durable responses in subsets of patients. By enhancing the ability of the immune system to identify and destroy cancer cells, ICIs have provided significant improvements in treatment outcomes across a range of tumor types. Despite these advances, resistance to ICIs remains a major barrier, driven by complex tumor-intrinsic and microenvironmental mechanisms. One area of growing interest is the role of lipid metabolism in cancer progression and immune evasion.
Cancer cells reprogram lipid metabolism to support survival under nutrient-deprived and hypoxic conditions, while stromal and immune cells in the Tumor MicroEnvironment (TME) also undergo lipid metabolic alterations that shape tumor-immune interactions. Targeting these pathways may represent a novel means to overcome immunosuppression and enhance response to ICIs.
Statins, widely prescribed for cardiovascular risk reduction, exhibit pleiotropic effects beyond lipid lowering, including modulation of PD-L1 expression, reprogramming of tumor-associated macrophages, and promotion of T-cell–mediated antitumor activity. These properties raise the possibility that statins may act synergistically with ICIs to improve patient outcomes.
Study Objective
Given the biologic rationale and conflicting results from prior studies, Liao and colleagues conducted a systematic review and meta-analysis to evaluate the prognostic impact of concomitant statin use in patients with cancer treated with ICIs. The goal was to determine whether this widely available and inexpensive class of drugs could augment the clinical benefits of immunotherapy.
Methods
- Search strategy: Comprehensive searches of PubMed, EMBASE, Cochrane Library, Web of Science, and major oncology conference proceedings were conducted through June 20, 2024.
- Inclusion criteria: Studies reporting Hazard Ratios (HRs) for Overall Survival (OS) and/or Progression-Free Survival (PFS) with statin use in ICI-treated patients.
- Study pool: 25 retrospective studies (N=46,154) included in the meta-analysis.
- Cancers represented: Non Small Cell Lung Cancer-NSCLC (8 studies), Renal Cell Carcinoma (3), Melanoma (1), Urothelial carcinoma (1), and Pan-cancer analyses (12).
- Patient characteristics: Statin use prevalence ranged from 8.7% to 50%. Study regions included Asia, Europe, and the United States.
- Endpoints: OS (in all 46,154 patients) and PFS (in 7,786 patients).
- Quality: 15 studies classified as high quality, 10 classified as moderate according to the modified NOS (Newcastle-Ottawa Scale).
Key Findings
- Overall Survival: Statin use was associated with a 20% reduction in mortality risk (HR 0.80; 95% CI, 0.71–0.92).
- Progression-Free Survival: A consistent benefit was observed (HR 0.80; 95% CI, 0.69–0.92).
- Subgroup analyses:
- By cancer type: Survival advantage was most pronounced in Renal Cell Carcinoma, while benefits were less consistent in NSCLC and Melanoma.
- By geography: OS benefit with statin use was noted in studies originating from Europe but not observed in studies conducted in Asia and US. Statin use was associated with improved PFS among Asian patients undergoing ICI therapy, but not observed in European and American patients.
Clinical Implications
- Mechanistic plausibility: Statins may enhance immunotherapy by downregulating PD-L1 expression, shifting macrophage polarization from an M2 to M1 phenotype, and reducing systemic inflammation.
- Accessibility: Statins are inexpensive, widely available, and well tolerated, positioning them as attractive adjuncts to ICIs.
- Limitations:
- All included studies were retrospective and observational.
- Potential confounding (eg, baseline comorbidities, concomitant medications).
- Lack of stratification by statin type, dose, or timing of initiation.
- Evidence of publication bias.
- Next steps: Well-designed Randomized Controlled Trials (RCTs) are essential to establish causality. A Phase II RCT investigating PD-1 inhibitors combined with statins in advanced NSCLC is already underway.
Conclusion
This meta-analysis provides the strongest evidence to date that concomitant statin therapy may improve both OS and PFS in patients with cancer receiving ICIs. While observational in nature, the findings highlight the potential of repurposing a widely used cardiovascular drug as an oncology adjuvant. If validated in prospective RCTs, statins could emerge as a low-cost, low-toxicity strategy to enhance immunotherapy efficacy across multiple cancer types, potentially shaping future treatment algorithms.
Takeaway for Oncologists
Concomitant statin use is associated with improved survival in ICI-treated patients across diverse cancers, with particular benefit seen in Renal Cell Carcinoma and in non-U.S. cohorts. Until prospective trials confirm these findings, clinicians should remain attentive to emerging data while considering statin therapy primarily for established cardiovascular indications.
Concomitant Statin Use and Survival in Patients With Cancer on Immune Checkpoint Inhibitors: A Meta-Analysis. Liao Y, Lin Y, Ye X, et al. JCO Oncol Pract. 2025;21:989-1000.
