Targeting SMARCAL1: A Promising Strategy for Enhancing Cancer Immunotherapy

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Targeting SMARCAL1: A Promising Strategy for Enhancing Cancer Immunotherapy

Targeting SMARCAL1: A Promising Strategy for Enhancing Cancer Immunotherapy

Cancer cells are often characterized by genomic instability, which means that during their rapid division and proliferation, the immense pressure of DNA replication makes the genome more prone to mutations and DNA damage.

This genomic instability can be exploited in anti-cancer strategies, as damaged DNA fragments leaking from the cell nucleus into the cytoplasm can trigger the cell’s innate immune sensors, leading to the release of chemokines that attract immune cells to the tumor vicinity. Subsequently, activated immune cells can eliminate the cancer cells before they become uncontrollable.

However, cancer cells are adept at appearing “innocent” to immune cells, with a typical tactic being the abundant expression of immune checkpoint molecules such as PD-L1, which can deceive immune cells.

This tactic of cancer cells has been uncovered by scientists. Immunotherapy, known as immune checkpoint inhibitors, can block the inhibitory signals that cancer cells send to immune cells, restoring the anti-tumor immune function of T cells. However, immune checkpoint inhibitors are not universally effective, as they fail to induce an immune response in a significant proportion of cancer patients, allowing cancer cells to evade immune surveillance.

A recent study published in the top academic journal *Cell* has exposed a new vulnerability of cancer cells. Scientists have identified a special protein that is involved in both suppressing the innate immune signal in cancer cells and mediating the immune checkpoint response induced by PD-L1. In other words, inhibitors targeting this dual-regulatory factor can deal a double blow to tumors, making immune checkpoint inhibitors more effective.

Targeting SMARCAL1: A Promising Strategy for Enhancing Cancer Immunotherapy

This crucial protein for cancer cells is called SMARCAL1, a member of the SNF2 family of DNA translocases. Researchers developed a CRISPR/Cas9-based screening method to identify factors that can simultaneously regulate the innate immune signal and the level of immune checkpoints in cells derived from breast cancer, ultimately discovering SMARCAL1.

In fact, SMARCAL1 functions through two different mechanisms. On one hand, during DNA replication, SMARCAL1 can maintain genome stability, reducing the cell’s endogenous DNA damage, thus helping cancer cells avoid triggering the cell’s innate immune sensors (i.e., the cGAS-STING signaling pathway) during growth. On the other hand, as a transcription regulator, SMARCAL1 can promote cancer cells to produce more PD-L1.

When researchers attempted to delete the gene expressing SMARCAL1 in melanoma cells or render this protein inactive, they achieved a dual effect: the activation of the innate immune response mediated by the cGAS-STING pathway and a decrease in the expression of immune checkpoint proteins, making cancer cells more visible to the immune system. Meanwhile, when using immune checkpoint inhibitors such as anti-PD-L1 antibodies, tumors lacking SMARCAL1 showed significantly increased sensitivity to immunotherapy, leading to a marked inhibition of tumor growth.

The research team further examined databases of samples from cancer patients and found that SMARCAL1 was overexpressed in most tumors, with its expression levels often corresponding to the levels of PD-L1 expression. In a cohort of patients receiving immune checkpoint inhibitor therapy, patients who had an immune response tended to have lower levels of SMARCAL1 expression. These findings suggest that “inhibiting SMARCAL1 may enhance the effectiveness of tumor immunotherapy,” the authors concluded.

In the final section of this paper, the researchers summarized that SMARCAL1 is a promising target for cancer immunotherapy.

Targeting SMARCAL1: A Promising Strategy for Enhancing Cancer Immunotherapy

Reference:

[1] Leuzzi et al., SMARCAL1 is a dual regulator of innate immune signaling and PD-L1 expression that promotes tumor immune evasion, Cell (2024), https://doi.org/10.1016/j.cell.2024.01.008

[2] A one-molecule immune evasion system: New discovery could land one-two punch against cancer. Retrieved Feb. 7, 2024 from https://medicalxpress.com/news/2024-02-molecule-immune-evasion-discovery-cancer.html

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