When Tumor Structure Shapes Immune Response
Immunotherapy has transformed cancer care, offering durable responses for some patients across a range of tumor types. But for many, including the majority of those with head and neck squamous cell carcinoma , those benefits remain largely out of reach.
Sonal Srivastava, PhD
Results from a new study led by researchers at Moffitt Cancer Center were presented at the American Association for Cancer Research Annual Meeting. The findings suggest the answer may lie not only in the immune system itself, but in the physical structure of the tumor microenvironment.
“Fewer than 20% of patients with recurrent or metastatic head and neck squamous cell carcinoma show clinical benefit from immune checkpoint blockade,” said Sonal Srivastava, PhD, presenting author on the study. “What stood out to us was that some tumors were highly infiltrated with immune cells yet still failed to respond. That told us that presence of these cells alone isn’t enough. Something else is shaping how those cells function.”
A Different Kind of Immune Checkpoint
The team turned its attention to the tumor microenvironment, specifically the extracellular matrix, the structural network that surrounds cells.
“In head and neck squamous cell carcinoma, that environment is often dense and fibrotic, and the extracellular matrix can be organized into highly aligned collagen fibers akin to that seen in the Achilles tendon,” said Antonio Amelio, PhD, lead author on the study.
Rather than acting as a simple barrier, researchers found that this remodeled collagen plays a more active role.
“The key takeaway is that fibrotic extracellular matrix remodeling can function as a form of immune checkpoint regulation,” Srivastava said.
The study identified what they describe as a collagen–ADGRG1 mechanosensory axis. In this model, stiff, aligned collagen fibers do not prevent immune cells from entering tumors. Instead, they trap them within the stromal regions and alter their behavior.
Through a signaling, these T cells adopt an exhausted, less effective state. The result is a tumor that appears immune-rich on the surface but is functionally immunosuppressed.
Why Biomarkers Fall Short
These findings help explain a persistent challenge in oncology: why commonly used biomarkers such as PD-L1 expression and tumor mutational burden do not reliably predict response to immunotherapy.
“Those markers don’t capture the physical and spatial constraints of the tumor microenvironment,” Srivastava said. “We’re showing that structure matters. Where immune cells are located and how they interact with their surroundings can fundamentally change their function.”
The study points to the potential for new types of biomarkers, ones that incorporate spatial and structural features of tumors. It also raises the possibility of combining immunotherapy with treatments that target the extracellular matrix itself.
A Model System with Broader Implications
Head and neck squamous cell carcinoma proved to be an ideal model for uncovering these dynamics. The disease often features a paradoxical combination of high immune infiltration and poor response to therapy, as observed in many HPV-negative tumors.
The team identified a distinct subtype of head and neck squamous cell carcinoma they describe as immune-enriched but fibrotic. In these tumors, immune cells are present but impaired, making it possible to study how physical structure can decouple immune presence from immune activity.
While the research focused on head and neck squamous cell carcinoma, the implications may extend far beyond it.
“We think this is a broadly conserved mechanism across fibrotic solid tumors,” Srivastava said. Similar collagen architectures are seen in cancers of the lung and breast, and the researchers observed that ADGRG1 is enriched in exhausted immune cells across these tumor types as well.
Rethinking the Tumor Microenvironment
Antonio Amelio, PhD
The findings challenge long-held assumptions about how tumors evade the immune system.
“Traditionally, fibrotic tumors were thought to suppress immune response by excluding immune cells,” Amelio said. “What we’re showing is a different model. Immune cells can enter, but the tumor effectively ‘programs’ them through its physical structure.”
This shift reframes the extracellular matrix as more than a passive scaffold. Instead, it emerges as an active regulator of immune cell fate, capable of not only directing where cells go but also how they behave.
The Power of Structure
One of the most surprising aspects of the study was what mattered most.
“We found that collagen organization, not abundance, was the dominant factor,” Srivastava said. “A structural feature like fiber alignment can activate a specific mechanosensory pathway and modulate immune response. That level of control has been largely underappreciated.”
As researchers continue to explore the intersection of tumor biology, physics and immunology, these insights could open new paths forward.
For patients who currently do not benefit from immunotherapy, understanding how the architecture of a tumor shapes immune response may be a critical step toward more effective, personalized treatment strategies.
