Unlocking New Possibilities for Immunotherapy for Colorectal Cancers

O’Neill A, Zakaria N, Bull C, Egan H, Corry SM, Leonard NA, et al. Stromal cells modulate innate immune cell phenotype and function in colorectal cancer via the Sialic acid/Siglec axis. Journal for ImmunoTherapy of Cancer. 2025;13:e012491. https://doi.org/10.1136/jitc-2025-012491

What the researchers set out to do

This study focused on a key challenge: in many bowel cancers, especially stromal-rich types (those with lots of supporting tissue, or stromal cells, around the tumor), immune therapies aren’t working as well as hoped. Researchers investigated how certain “support” cells within the tumor (called stromal cells) may be actively helping the cancer by suppressing the body’s immune system. Then they investigated how to turn the immune system back on again in these hard-to-treat cancers.

What they found

• The stromal cells in the tumor environment showed high amounts of a sugar-coating on their surfaces (called “sialic acids”). These sugar signals were found to “turn off” important immune cells.

• These sugar signals engage a kind of “brake” receptor on immune-cells (called “Siglec” receptors). When this binding happens, immune cells such as macrophages and natural-killer (NK) cells are less able to attack the cancer.

• Crucially: in lab models (both human cells in dishes and mice), when the researchers removed or blocked that sugar-coating on the stromal cells, the immune cells regained strength:

  • Macrophages became more active.

  • NK cells showed more “killer function”.

  • Tumor growth slowed in models where that sugar signal was disrupted.

    
    

Why this matters for patients

• New treatment directions: This study identifies a previously under-appreciated mechanism by which cancers dampen the immune system. Blocking that mechanism gives a new target for future therapies.

• Personalized hope: For patients whose tumors have a lot of stromal (support) tissue and have been resistant to other immune therapies, this could open up new options.

• More effective combinations: Rather than relying only on existing immune therapies, treatments could be enhanced by adding a “stroma-sugar-blocking” step.

• A clearer path forward: Because this mechanism was identified and validated in models, drug developers now have a roadmap to develop real therapies — and that means faster translation toward human trials.

What comes next

• Researchers will need to test drugs/agents that safely block those sugar-signals or Siglec interactions in humans.

• Clinical trials will need to determine: Which patient types benefit most? What are the side-effects? How does this blocking strategy combine with existing therapies?

• Biomarker work: It will be important to identify which tumors have high stromal sugar-coating or high Siglec engagement, so that patients likely to benefit can be selected.

Take-home message

This isn’t a cure yet, but it’s a step forward. It shows that even in cancers where the immune system has been “turned off” by the tumor microenvironment, we may be able to turn it back on. For patients and caregivers, this means new hope: new pathways being developed, new clinical trials on the horizon, and a more active future for immune-based treatments.

We at the Abdominal Cancers Alliance are excited about these findings — and will keep watching for how this research becomes real-world treatments.

Explore the Study

jitc.bmj.com

Stromal cells modulate innate immune cell phenotype and function in colorectal cancer via the Sialic acid/Siglec axis

Background The immunosuppressive tumor microenvironment reduces immune response effectiveness in stromal-rich tumors, including consensus molecular subtype 4 colorectal cancer (CRC). Mesenchymal stromal cells (MSCs), precursors to cancer-associated fibroblasts (CAFs), promote cancer progression by suppressing anti-tumor immune responses. Hypersialylation of glycans on tumors engages Siglec receptors on immune cells, driving immune dysfunction, but its role in stromal-mediated suppression of innate immunity remains unclear.Methods Sialylation, Sialic acids and Siglec ligands were measured on CRC tissue, primary human normal-associated fibroblasts (NAFs), CAFs, and tumor-conditioned MSCs (MSC TCS) using transcriptional profiles, immunohistochemistry and flow cytometry, respectively. The effect of stromal cell sialylation on macrophages and NK cells was assessed in ex vivo human primary stromal and immune cell co-cultures, and expression of Siglec-10 and immune cell phenotype markers and function was measured by flow cytometry and real-time imaging. Using an immunocompetent Balb/c CT26 mouse model, we induced tumors with/without conditioned stromal cells, with/without pretreatment of stromal cells with sialyltransferase inhibitor (3FAX) or sialidase (E610). We assessed the effect of stromal cell sialylation on macrophages and NK cells in the tumor and secondary lymphoid tissues by flow cytometry.Results Stromal cells, including CAFs, in CRC tumors are highly sialylated compared with epithelial cancer cells and are associated with high expression of the sialyltransferase ST6GALNAC6. Genetic knockdown of ST6GALNAC6 reduced the expression of stromal cell Siglec-10 ligands in MSCs. CAFs and MSCTCS induced Siglec-10 on macrophages and NK cells and impaired macrophage phagocytosis and NK cell cytotoxicity. Sialidase treatment reduced Siglec-10 expression, restoring macrophage and NK cell antitumor functions. In vivo and ex vivo, desialylation of stromal cells increased macrophage activation (CD11b+CD80+) and reduced immunosuppressive marker expression (CD206, PD-L1, Siglec-G) in lymphoid tissues, indicating sustained systemic anti-tumor immunity. Intratumoral NK cells exhibited high Siglec-G expression and impaired cytotoxicity, and granzyme B expression significantly increased with sialidase treatment of stromal cells. In an inflammatory tumor model, inflammatory tumor-conditioned MSCs (MSCiTCS) promoted metastasis and Siglec-G induction on NK cells and macrophages, both reversed by sialyltransferase inhibition, underscoring the effects of stromal modulation of innate immune cell function in inflammatory tumors.Conclusions Stromal cell sialylation modulates innate immune suppression in CRC via the sialic acid/Siglec axis. Targeting stromal sialylation restores NK cytotoxicity and macrophage activation, offering novel insights that may shape therapeutic strategies for reversing immunosuppression in stromal-rich tumors.

Disclaimer: This summary is intended for educational purposes and does not replace medical advice. Always consult your healthcare provider about your specific case.