In a breakthrough study unveiled in the latest volume of BMC Cancer, researchers have uncovered a compelling mechanism by which metformin, a widely used antidiabetic medication, exhibits potent anti-cancer effects against bladder cancer. Central to this discovery is metformin’s ability to downregulate PD-L1, an immune checkpoint protein pivotal in tumor immune evasion and progression. This study, conducted using a sophisticated orthotopic bladder cancer mouse model, underscores metformin’s promising role as a novel therapeutic agent targeting the PD-L1/PD-1 axis intrinsic to bladder tumor growth.

Programmed death-ligand 1 (PD-L1) has emerged as a critical immunoregulatory protein that cancer cells exploit to subvert the host immune response. Its interaction with PD-1 receptors on T cells effectively dampens immune surveillance, enabling tumors to thrive unchecked. While immune checkpoint blockade therapies targeting PD-L1 and PD-1 have revolutionized oncology, their clinical efficacy, unfortunately, remains limited by low response rates in bladder cancer. This notable challenge has led scientists to investigate alternative or complementary approaches to modulate PD-L1 expression and thereby enhance antitumor activity.

Metformin, traditionally employed in managing type 2 diabetes, has piqued oncological interest due to epidemiological links suggesting a reduced incidence and improved prognosis of various cancers, including bladder cancer, among diabetic patients taking the drug. However, the precise cellular and molecular mechanisms underlying metformin’s anticancer effects have been incompletely understood. The current study bridges this critical knowledge gap by elucidating metformin’s role in directly targeting PD-L1 expression and modulating tumor cell proliferation within the bladder microenvironment.

The research team implemented a syngeneic orthotopic bladder cancer model using immunocompetent C57BL/6 mice, a system that closely simulates the human disease and maintains intact immune interactions. This approach enabled precise evaluation of metformin’s therapeutic efficacy and biological impact on tumor progression. Prior to therapeutic administration, the investigators conducted a rigorous maximum tolerated dose (MTD) assessment, establishing a safe yet effective dosage of 150 mg/kg/day—critical for translational relevance and minimizing systemic toxicity.

Notably, quantitative analyses revealed that bladder tumor tissues from these mice manifested significantly elevated levels of PD-L1 gene and protein expression relative to controls, highlighting the ligand’s integral role in bladder cancer pathogenesis. Detailed in vitro assays further corroborated these findings, showing that metformin treatment resulted in marked inhibition of PD-L1 expression in MB49, a murine bladder cancer cell line, coupled with reduced cell proliferation as assessed by tetrazolium-based viability tests.

In vivo administration of metformin at the established dose imparted several beneficial outcomes. Treated mice exhibited a substantial decrease in tumor burden, attenuated cancer-associated cachexia, and improved overall survival—hallmarks indicative of the drug’s multifaceted antitumor activity. Particularly compelling was the observation of a dose-dependent suppression of tumor-induced PD-L1 upregulation, suggesting that metformin interrupts the feedback mechanisms that tumors utilize to maintain immunosuppression and promote intrinsic oncogenic signaling.

These findings collectively advance a paradigm in which bladder cancer progression is intricately linked to PD-L1 not merely as an extrinsic immune checkpoint but also as a driver of intrinsic tumor growth factors. By effectively downregulating PD-L1, metformin disrupts these oncogenic pathways, thereby not only reviving immune-mediated cytotoxicity but also directly thwarting cancer cell proliferation. This dual action offers a promising avenue for therapeutic intervention that could complement existing immunotherapies, potentially enhancing response rates and clinical outcomes.

The study’s utilization of a syngeneic orthotopic mouse model lends significant translational weight, reflecting the complex interactions between tumor cells and the host immune system more accurately than traditional xenograft models. This fidelity is paramount when investigating immune checkpoint proteins like PD-L1, whose tumor-mediated regulation is profoundly influenced by the tumor-immune milieu. The ability of metformin to exert its effect within this context supports its candidacy for clinical evaluation in bladder cancer therapy.

Moreover, as metabolic dysregulation is a hallmark of cancer, metformin’s established role as a modulator of cellular metabolism through AMP-activated protein kinase (AMPK) activation may synergize with its PD-L1 downregulation capacity. This metabolic reprogramming could sensitize tumor cells to immune attack and inhibit proliferative signaling pathways, underscoring the drug’s multifaceted mechanism of action. Future studies will need to dissect these interconnected pathways to optimize metformin’s application as an anti-cancer agent.

Given the high prevalence and significant morbidity associated with bladder cancer, the identification of metformin as a therapeutic agent capable of both dampening immunosuppressive signaling and limiting tumor growth is particularly encouraging. The simplicity of repurposing an existing, well-characterized pharmaceutical with a favorable safety profile offers tangible benefits in accelerating the translation of these findings to clinical practice.

In addition to bladder cancer, mounting evidence suggests the potential utility of metformin in various malignancies characterized by aberrant PD-L1 expression. This positions the drug within a broader landscape of immune-oncology, where metabolic modulators may serve as adjuncts or alternatives to current immune checkpoint inhibitors. Personalized treatment regimens integrating metformin could thus be tailored based on tumor PD-L1 status and patient metabolic profiles.

The advancement of immunometabolic therapies exemplified by this work opens new horizons in the fight against cancer. It highlights the value of integrating metabolic interventions with immune checkpoint targeting to overcome resistance mechanisms and improve patient survival. As translational research continues to uncover the nuances of tumor biology, agents like metformin that marry metabolic and immune modulation represent a promising frontier.

This study paves the way for future clinical trials to validate metformin’s efficacy and delineate optimal dosing strategies in human bladder cancer patients. It also prompts exploration into combinatorial regimes incorporating metformin with established immunotherapy agents to potentiate anticancer immune responses. Understanding the molecular crosstalk between metabolism and immune regulation remains crucial to unlocking the full potential of such combination therapies.

In conclusion, this research highlights metformin’s capacity to serve as a powerful anticancer agent through its inhibition of PD-L1 expression and subsequent suppression of tumor growth in bladder cancer. By mitigating cancer cachexia, shrinking tumor volume, and enhancing survival in vivo, metformin emerges as a readily available, dual-function therapeutic contender. These findings reinvigorate interest in metabolic drugs within oncology and underscore the critical interplay between cancer metabolism and immune escape mechanisms.

As the cancer research community seeks innovative strategies to augment immunotherapy efficacy and patient outcomes, metformin stands out as a beacon of hope, exemplifying how reexamining established medications can yield novel and clinically impactful insights. This study definitively positions metformin at the nexus of immunology and metabolism, promising a new horizon in bladder cancer management.

Subject of Research: The study investigates the anti-cancer effects of metformin on bladder cancer, focusing on its mechanism of PD-L1 downregulation using a syngeneic orthotopic mouse model.

Article Title: Metformin as an anti-cancer agent against bladder cancer acts via PD-L1 downregulation in an orthotopic mouse model

Article References:
Yeh, CC., Tsai, PC., Song, YD. et al. Metformin as an anti-cancer agent against bladder cancer acts via PD-L1 downregulation in an orthotopic mouse model.
BMC Cancer 25, 1534 (2025). https://doi.org/10.1186/s12885-025-14930-2

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14930-2

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