Immunotherapy has revolutionized cancer treatment over the past decade. However, in hepatocellular carcinoma (HCC), the most common type of liver cancer, many patients still fail to achieve durable responses to immune checkpoint inhibitors such as anti-PD-1 or anti-PD-L1 therapies. Although drugs such as pembrolizumab, nivolumab, and tislelizumab can reactivate antitumor T cells, their effectiveness is often limited by a fundamental challenge: the immunosuppressive tumor microenvironment.

A recent study proposes a surprisingly simple strategy to overcome this barrier: the administration of sodium bicarbonate directly into the tumor. The key lies in its well-known role as a pH regulator, through which researchers found that bicarbonate can profoundly modify tumor biology, activate critical immune mechanisms, and significantly improve responses to anti-PD-1 therapy.

 

The problem of tumor acidity

Solid tumors often develop a highly acidic environment due to their altered metabolism. Cancer cells consume large amounts of glucose and produce lactic acid even in the presence of oxygen, a phenomenon known as the Warburg effect.

This acidification is not merely a metabolic byproduct. Numerous studies have shown that an acidic tumor microenvironment promotes tumor progression by inhibiting T-cell activity (specialized cells responsible for destroying cancer cells), reducing dendritic cell function (cells responsible for alerting the immune system), and facilitating multiple mechanisms of immune evasion.

For this reason, researchers have spent years exploring strategies to neutralize tumor acidity. However, most approaches have focused solely on modifying extracellular pH. The new study proposes something different: using bicarbonate to directly alter the internal metabolism of tumor cells and trigger a more powerful immune response.

 

Bicarbonate affects mitochondria

One of the most interesting findings of the study is that bicarbonate appears to act through mitochondria, the organelles responsible for cellular energy production.

Researchers observed that bicarbonate-induced alkalinization (an increase in pH) alters membrane behavior, causes mitochondrial swelling, and promotes mitochondrial rupture. As a result, fragments of mitochondrial DNA (mtDNA) escape into the cytoplasm.

This event is particularly important because released mitochondrial DNA acts as a danger signal. Cells detect it through a system known as cGAS-STING, one of the major innate immune surveillance pathways. This immediately triggers a molecular cascade that culminates in the production of type I interferons, particularly IFN-α and IFN-β, molecules that are essential for alerting and activating the immune system. In simple terms, the cell detects internal damage and signals the immune system to inspect it.

As a result, bicarbonate appears to transform metabolic stress within tumor cells into an inflammatory signal capable of attracting the attention of the immune system and promoting tumor destruction.

 

Immunogenic Cell Death: When cancer cells “announce” their own death

In addition to activating the cGAS-STING pathway, the study demonstrated that bicarbonate induces a phenomenon known as immunogenic cell death (ICD).

Not all forms of cell death generate an immune response. In many cases, cells simply disappear without causing inflammation. However, during ICD, tumor cells release signals capable of recruiting and activating immune cells.

Among these signals are:

• ATP release
• Surface exposure of calreticulin (CRT)
• HMGB1 release
• Production of type I interferons
  

These molecules function as alarm signals that attract dendritic cells and promote the activation and education of T lymphocytes.

Researchers observed this phenomenon not only in liver cancer cells but also in breast cancer and colorectal cancer models, suggesting that the mechanism may have broader applications.

 

Turning “Cold” tumors into “Hot” tumors

One of the greatest challenges of modern immunotherapy is that many tumors contain very few infiltrating immune cells. These tumors are often referred to as “cold tumors” and tend to respond poorly to immune checkpoint inhibitors.

Activation of the STING pathway and induction of ICD generate multiple signals capable of attracting immune cells into the tumor. Bicarbonate appears to convert an immunologically invisible tumor into one that is much more detectable by the immune system.

 

Why combine it with anti-PD-1 therapy?

PD-1 inhibitors work by removing the “brakes” that limit T-cell activity. However, these treatments do not necessarily increase the number of immune cells that enter the tumor.

For this reason, researchers proposed a simple hypothesis: if bicarbonate can attract more immune cells into the tumor, and anti-PD-1 antibodies restore the function of those cells, the two treatments could complement each other.

Results in animal models supported this idea. In liver, breast, and colon cancer models, the combination of bicarbonate and anti-PD-1 therapy produced significantly greater tumor suppression than either treatment alone.

 

Figure 1. Bicarbonate-induced cellular stress promotes mitochondrial damage and activation of innate immune signaling pathways, leading to immunogenic cell death, release of danger signals, and increased immune cell infiltration within the tumor microenvironment. 

 

Initial clinical results

The preclinical findings led researchers to evaluate this strategy in patients with advanced hepatocellular carcinoma.

The study included 30 patients treated with hepatic arterial bicarbonate infusion combined with tislelizumab, an anti-PD-1 antibody. Most patients had advanced disease, large tumors, or vascular invasion, characteristics associated with poor prognosis.

The results were highly encouraging. More than 93% of patients experienced measurable tumor reduction, including 53.3% who achieved a complete response and 40% who achieved a partial response. In addition, patients remained progression-free for a median of 31 months.

Tumor biopsies showed significantly greater T-cell infiltration compared with patients treated with immunotherapy alone.

Although these results should be interpreted cautiously due to study limitations, they represent a highly promising clinical signal.

 

A new category of immunometabolic adjuvants

Perhaps the most interesting aspect of this work is that it introduces an emerging concept in oncology: immunometabolic adjuvants.

Traditionally, cancer therapies have been classified as chemotherapy, immunotherapy, or targeted therapy. However, there is increasing evidence that tumor metabolism and immune responses are deeply interconnected.

Bicarbonate appears to act precisely at this intersection. On one hand, it alters tumor cell energy metabolism through mitochondrial damage. On the other hand, it converts these metabolic alterations into signals capable of activating both innate and adaptive immunity.

This dual mechanism may help explain why the combination with PD-1 inhibitors produced such remarkable results.

The available data point to a fascinating possibility: a simple, inexpensive, and widely available molecule could become a valuable tool for significantly enhancing the efficacy of PD-1 inhibitors in liver cancer and potentially other solid tumors.

 

This article is intended solely for educational and informational purposes. It is not intended to provide medical advice, diagnosis, or treatment recommendations. Readers should consult qualified healthcare professionals regarding any medical concerns or decisions related to their health.

 

Main reference:

Wang, D., Jin, K., Ying, C., Li, B., Zhang, G., Li, J., Chen, L., Chao, M., & Hu, X. (2026). Intratumoral bicarbonate functions as an adjuvant to potentiate PD-1 blockade in hepatocellular carcinoma. Oncogene, 1–16. https://doi.org/10.1038/s41388-026-03836-3 

 

Other reference:

Galluzzi, L., Buqué, A., Kepp, O., Zitvogel, L., & Kroemer, G. (2017). Immunogenic cell death in cancer and infectious disease. Nature reviews. Immunology, 17(2), 97–111. https://doi.org/10.1038/nri.2016.107 

Pilon-Thomas, S., Kodumudi, K. N., El-Kenawi, A. E., Russell, S., Weber, A. M., Luddy, K., Damaghi, M., Wojtkowiak, J. W., Mulé, J. J., Ibrahim-Hashim, A., & Gillies, R. J. (2016). Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy. Cancer research, 76(6), 1381–1390. https://doi.org/10.1158/0008-5472.CAN-15-1743