Researchers Identify B Cells as Driver of Immunotherapy Resistance in Liver Cancer

Despite major advances in immunotherapy, most patients with hepatocellular carcinoma (HCC) fail to respond to current immune checkpoint inhibitors. New research led by investigators now at Houston Methodist Hospital suggests an unexpected immune cell population — tumor-associated B cells — may be a key driver of resistance and a promising therapeutic target.

The study, led by Dr. Dan Duda, Ph.D., and published in the journal Nature Communications, shows that B cells infiltrating liver tumors can suppress the anti-tumor activity of T cells, limiting the effectiveness of immunotherapy.

In preclinical models, selectively disrupting this B-cell–mediated immunosuppression significantly enhanced the activity of both immune checkpoint blockade and STING-based immune therapies.

The findings highlight a previously underappreciated component of the liver tumor microenvironment and suggest new combination strategies that could expand the reach of immunotherapy for patients with advanced liver cancer.

An immune paradox inside liver tumors

Immune checkpoint blockade (ICB) therapies, such as PD-1 and PD-L1 inhibitors, work primarily by reinvigorating cytotoxic T cells that recognize and destroy tumor cells. In hepatocellular carcinoma, these therapies — often combined with anti-angiogenic drugs — have transformed systemic treatment options in recent years.

Yet clinical response rates remain modest. More than 70% of patients with advanced HCC ultimately fail to respond or develop resistance to ICB therapies.

Most research into this resistance has focused on T cells and other well-known immune suppressors such as regulatory T cells or myeloid-derived suppressor cells. However, the new study reveals that B lymphocytes — traditionally known for producing antibodies — can also play a powerful regulatory role inside tumors.

By analyzing multiple RNA sequencing datasets from liver cancer models treated with immunotherapy, researchers found that immune checkpoint blockade consistently increased infiltration of both CD8+ T cells and B cells within tumors. While the T-cell expansion was expected, the rise in B cells was more surprising.

Further investigation showed that many of these infiltrating B cells adopted an immunosuppressive phenotype, releasing anti-inflammatory cytokines such as IL-10 that dampen anti-tumor immunity.

Playing for the wrong side

Using mouse models that mimic human HCC — including tumors arising in fibrotic liver tissue — investigators demonstrated that immunotherapy and STING agonists both trigger an influx of B cells into tumors.

These B cells often organized into clusters resembling tertiary lymphoid structures, immune aggregates sometimes seen in chronic inflammatory diseases and cancers. But in this context, the B-cell populations appeared to limit therapeutic responses.

When researchers experimentally depleted B cells, the results were striking.

Combining B-cell depletion with immune checkpoint blockade significantly delayed tumor growth and improved survival compared with immunotherapy alone. Similar results were observed when B-cell depletion was paired with activation of the STING pathway — an innate immune signaling mechanism that stimulates type I interferon responses and is being explored as an anti-cancer strategy.

In highly aggressive liver cancer models prone to metastasis, the combination therapy not only slowed tumor progression but also reduced lung metastases.

A new immune checkpoint on B cells

The researchers also identified a potential molecular target driving this immunosuppressive B-cell activity.

The work highlights TIM-1, an immune checkpoint receptor expressed on a subset of regulatory B cells. Tumors treated with immunotherapy or STING agonists showed increased expression of TIM-1 and higher levels of regulatory cytokines associated with immune suppression.

Blocking TIM-1 signaling alongside STING activation produced stronger anti-tumor responses than either therapy alone, enhancing CD8+ T-cell activity and slowing tumor progression in immunotherapy-resistant models.

The results suggest that TIM-1 could serve as both a biomarker of resistance and a therapeutic target.

Expanding the immunotherapy playbook

Importantly, B-cell targeting alone did not affect tumor growth, indicating that these cells become therapeutically relevant primarily in the context of immune activation.

But when combined with checkpoint blockade and innate immune stimulation, removing B-cell-mediated suppression dramatically amplified treatment responses. In some models, a multi-drug combination of STING activation, checkpoint inhibition and B-cell targeting eradicated tumors entirely and generated durable immune memory.

The study also found that gene signatures associated with TIM-1-positive B cells correlated with survival in human liver cancer datasets, suggesting that the mechanisms observed in mice may be clinically relevant.

The findings add to a growing body of evidence that tumor microenvironments — not just cancer cells themselves — determine how patients respond to immunotherapy.

While B cells can play beneficial roles in many cancers by presenting antigens and supporting immune activation, this work demonstrates that specific B-cell subsets may instead promote immune escape in liver cancer.

The implication for clinicians and researchers: Targeting immunosuppressive B cells — or selectively reprogramming them — could help unlock more durable responses for patients with this challenging disease.