Immunotherapy has transformed cancer treatment, but in liver cancer—including hepatocellular carcinoma (HCC)—its efficacy remains limited. Even powerful immune-activating strategies often fail to produce durable responses. The illustration below summarizes a key reason why: the immune system can activate both tumor-fighting and tumor-suppressing pathways at the same time.

When Immune Activation Backfires

STING agonists are drugs designed to stimulate innate immunity. By activating the STING pathway, they trigger type I interferon signaling, improve blood vessel function in tumors (vessel normalization), and promote immune cell infiltration. In HCC models, STING activation also drives the formation of tertiary lymphoid structures (TLS)—organized immune cell clusters that can support anti-tumor immunity.

However, STING activation has a critical downside: it increases B-cell infiltration into the tumor microenvironment. Among these B cells is a regulatory subset known as TIM-1⁺ regulatory B cells (Bregs). These cells produce IL-10, an immunosuppressive cytokine that dampens CD8⁺ T-cell activity. As shown in the upper-left panel, this creates a brake on the immune response just as it is being activated.

The Dual Role of B Cells

B cells are not inherently harmful. In some contexts, they contribute to antigen presentation and help organize effective immune responses within TLS. But in HCC treated with STING agonists or immune checkpoint blockade, the balance shifts. Regulatory B cells accumulate, suppress cytotoxic T cells, and limit the overall effectiveness of therapy.

This helps explain a long-standing puzzle: why strong immune activation does not always translate into tumor control.

Targeting B Cells Unlocks Anti-Tumor Immunity

The lower-right panel illustrates the key therapeutic insight. When B cells are depleted, or when TIM-1 is blocked (using anti-TIM-1 antibodies), the suppressive arm of the immune response is removed. In combination with STING agonism and immune checkpoint therapy (such as anti–PD-1/VEGFR2 antibodies), this leads to:

• Normalization of tumor vessels

• Enhanced CD8⁺ T-cell infiltration

• Expansion of CD8⁺ memory T cells

• Durable tumor control

• Prevention of metastatic spread and decreased disease morbidity

Anti-Metastatic Effects

Distant metastasis—including to the lungs—is a major cause of mortality in liver cancer. The lower-left panel highlights a striking finding: STING agonism combined with B-cell targeting significantly reduces lung metastases and pleural effusions. This anti-metastatic effect is rarely seen among current HCC immunotherapies and indicates that immune reprogramming can act systemically, not just at the primary tumor site.

A New Therapeutic Balance

Together, these findings show that successful immunotherapy in liver cancer is not just about “turning immunity on.” It is about shaping the immune response—amplifying tumor-killing T cells while restraining immunosuppressive B-cell pathways.

Combined STING activation with B-cell targeting leads to durable anti-tumor and anti-metastatic immunity.

This balance may be the key to converting immunotherapy-resistant liver cancers into long-term responders.