Circular RNAs and the tumor microenvironment: key elements of cancer progression and therapeutic innovation
Why the tumor microenvironment matters more than ever
At the 2025 AACR Annual Meeting, researchers highlighted how manipulating the tumor microenvironment (TME) could improve responses to immunotherapy and reduce resistance in aggressive cancers like glioblastoma and metastatic gastric cancer1. These findings underscore a growing realization in oncology: cancer is not just a disease of rogue cells, but of the ecosystem they inhabit. Cancers develop gradually through multiple cellular and molecular changes in the body, and most cancers arise late in life, often after the accumulation of abnormalities over time.
The TME includes a dynamic mix of tissue compartments, immune cells, stromal cells, blood vessels, and signaling molecules surrounding and interacting with tumor cells2. Depending on how it evolves, this environment can either suppress or support tumor growth. But what if a new class of RNA molecules could help us decode, and even reshape, this complex system? Notably, circular RNAs (circRNAs) may also play roles in other diseases beyond cancer.
What are circRNAs? A quick primer
CircRNAs are a unique type of non-coding RNA that, unlike traditional linear RNAs, form covalently closed loops. This circular structure makes them unusually stable in cells and bodily fluids, allowing them to persist longer than their linear counterparts3-4.
Once thought to be transcriptional noise, circRNAs are now recognized as abundant and functionally diverse. Endogenous circRNAs can undergo circRNA translation, often through internal ribosome entry site (IRES)-mediated translation, which allows translation initiation independent of the 5' cap structure.
The translation efficiency of circRNAs can vary, and peptides encoded by circRNAs may have unique biological functions. Their stability and specificity make them promising candidates for biomarkers and therapeutic targets5.
Tumor microenvironment and immune suppression: The hidden barrier
The tumor microenvironment is more than a passive backdrop for cancer cells; it is an active, ever-changing ecosystem that influences the body’s ability to fight cancer6. Various cell types, including immune cells, endothelial cells, and fibroblasts, interact with cancer cells, shaping tumor development and progression.
A significant challenge posed by the tumor microenvironment is its ability to suppress the immune system. Cancer cells evade immune detection by expressing checkpoint molecules like PD-L1, which bind to PD-1 receptors on immune cells and halt the immune response, allowing unchecked tumor growth. In addition, the environment recruits immune suppressive cells, such as regulatory T cells and myeloid-derived suppressor cells, weakening the body’s defenses7.
The extracellular matrix (ECM), a network of proteins and polysaccharides, plays a vital role by providing structural support and acting as a barrier that hinders immune cell infiltration and attack on cancer cells. As tumors grow, the ECM can be remodeled to foster an environment that supports tumor growth, survival, and therapy resistance.
Endothelial cells, lining blood vessels, are crucial to the tumor microenvironment as they drive angiogenesis, the formation of new blood vessels supplying tumors with oxygen and nutrients. These vessels also serve as pathways for metastatic cells, enabling cancer to spread to distant tissues.
As researchers explore the signals and cell types within the microenvironment, it is evident that targeting this barrier is key to developing effective therapies. Understanding how cancer cells manipulate their environment and how molecules like circRNAs play a role brings us closer to innovative treatments that can counteract even the most resilient tumors.
The intersection: how circRNAs influence the tumor microenvironment
Emerging research suggests that circRNAs are not passive byproducts of gene expression8. Instead, they actively shape the TME through several mechanisms:
- miRNA sponging: Many circRNAs contain binding sites for miRNAs, preventing these small RNAs from downregulating their target genes. For example, a circRNA that sponges a tumor-suppressive miRNA could promote immune evasion or angiogenesis9.
- Protein scaffolding: Some circRNAs serve as platforms that bring together proteins involved in signaling pathways, enhancing or inhibiting their activity10. CircRNAs can sometimes increase the affinity between signaling molecules, such as p53, H2AX, and Bclaf1, thereby modulating protein-protein interactions.
- Transcriptional regulation: Certain circRNAs can interact with transcription factors or chromatin-modifying complexes, influencing gene expression in both tumor and stromal cells11.
CircRNAs can also influence metabolic reprogramming in tumor cells, affecting their ability to form tumors and adapt to the TME.
Consider circRNAs as molecular switches or amplifiers, small yet powerful regulators capable of tipping the balance of the TME toward tumor progression or suppression.
Real-world impact: circRNAs in cancer progression and therapy
As mentioned, several circRNAs have been linked to specific cancers and their microenvironments. Here are specific examples:
- Breast cancer: circFBXW7 has been shown to suppress tumor growth by sponging oncogenic miRNAs, while circAGFG1 promotes immune evasion by regulating PD-L1 expression12.
- Lung cancer: circPRKCI enhances tumor proliferation and resistance to EGFR inhibitors by modulating the PI3K/AKT pathway13.
- Glioma: circSMARCA5 is associated with angiogenesis and blood-brain barrier disruption, contributing to tumor invasiveness14.
- CircRNAs have also been implicated in blood-related cancers, including those affecting red blood cells, such as certain leukemias and lymphomas.
These molecules influence key aspects of the TME by regulating immune checkpoint molecules or cytokine production, thereby contributing to immune evasion. They also play a role in angiogenesis by modulating VEGF signaling and affecting endothelial cell behavior, highlighting the importance of blood supply in supporting tumor growth. In addition, they contribute to drug resistance through interactions with drug transporters or by activating survival pathways15. Cell culture and mouse models, including studies in mice, are commonly used to investigate how circRNAs induce tumor formation and progression, providing insights into the molecular mechanisms involved16.
Why this matters: implications for research and medicine
The study of circRNAs in the context of the TME opens new avenues for translational research. By targeting circRNAs that regulate immune suppression or therapy resistance, researchers may be able to enhance the effectiveness of existing treatments like checkpoint inhibitors or chemotherapy17.
In recent years, novel assays and diagnostic tools have been developed to detect and study circRNAs, further advancing the field. These approaches could lead to more precise diagnostics and personalized therapies that adapt to the evolving TME18.
What’s next? The future of circRNA research
Despite their promise, several challenges remain:
- Detection: CircRNAs often share sequences with linear RNAs, making them difficult to distinguish without specialized tools19.
- Functional validation: Proving that a circRNA has a specific role in cancer requires rigorous in vitro and in vivo studies, and often involves several rounds of experimentation to confirm circRNA function.
- Delivery systems: Targeting circRNAs in specific cells or tissues remains an obstacle for therapeutic development20.
However, new technologies are helping to overcome these barriers. Spatial transcriptomics allows researchers to map circRNA expression within the TME, while CRISPR-based tools enable precise editing of circRNA-producing genes. These innovations could accelerate the discovery of circRNA functions and their therapeutic potential21.
As our understanding of the TME deepens, circRNAs are emerging as key players in the dialogue between cancer and its environment. By studying these molecules, we may uncover new strategies to disrupt that conversation and tip the balance in favor of the patient.
References
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