Metaboimmunotherapy: a revolutionary concept of living with cancer

Chris Y.H. Tan; Mark Ellisman; Colin Hill; Wenyi Wei; Joseph R. Kates

doi:10.15302/vita.2026.01.0004

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Metaboimmunotherapy: a revolutionary concept of living with cancer

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The relevance of history and the full impact of this thesis with the recent transformative research advances emerging from Sheng-Cai Lin’s group at Xiamen University may transcend the discovery of glucose metabolism in the past century. They have found that even modest modulation of metabolism, governed by rises and falls in glucose, can trigger the body’s intrinsic immunity to combat cancer, enabling cancer-bearing mice to live to a ripe old age in wellness.

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Hans Krebs and Otto Warburg, highly acclaimed in their time, painstakingly defined the basic metabolic pathways involved in glycolysis and respiration with their inbuilt regulatory mechanisms underlying all living creatures. George Beadle and Edward Tatum at Caltech (preceded by Archibald Garrod in England) linked genes to enzymes, thereby tying genetics to metabolism. This was followed by the work of Avery, McCloud, and McCarty to identify the chemical nature of a gene and the subsequent elucidation of the provocative structure of DNA. From this sprang the field of molecular genetics and molecular biology, and eventually genomics. Somewhere in this historical progression, the fundamental role of metabolism became overshadowed by the central dogma, especially as it pertained to distinguishing how metabolism vs genetic regulatory mechanisms govern cellular and organismal processes and human disease. Fast forward nearly a century, Lin and his group discovered the role of glucose as a key determinant in the physiology of innate homeostasis. Glucose, abundant as it is, acts as a ligand-like molecule in the form of its glycolytic intermediary metabolite fructose-1-6 bisphosphate^1,2. High glucose sustains mTORC1, whereas low glucose activates AMPK, with activation of AMPK and inhibition of mTORC1 enabling extension of health-span and lifespan³. The pathway for sensing glucose operates at the organelle of the lysosome⁴. A spatiotemporal understanding of this regulation could be attained by the use of advanced technologies such as the multiple-scale microscopy of Mark Ellisman. Teleologically, frugality has long been practiced in the real world to ensure food sustainability. Against this backdrop, a set of discoveries from the Lin group provides a well-conceived rationale backed by impressive experimental evidence for a central regulatory role of metabolism in controlling major physiological processes at the level of cells and organisms. Intuitively, it makes sense that the nutritional status of an organism should impinge on various physiological functions, exerting controls that allow the organism to compensate for impending nutrient/energy crises. It is therefore not surprising that metabolic control processes were deployed early on as cellular survival mechanisms and that they could plausibly still represent highly potent underlying influences on cellular physiology and disease progression, as well as on fitness, thereby influencing health span and lifespan. Though this perspective focuses on one type of cancer, the underlying metabolic/physiological mechanisms may apply to a broad range of normal processes of the body and extend into management and probably the induction of disease states.

The idea that cancer results from a failure of immune surveillance is not new, yet it remains a conundrum as to how the immune system is escaped or mobilized. Our immune system can identify and eliminate cancerous cells, and it is the escape of nascent cancer cells from this surveillance mechanism that allows them to survive, proliferate, and ultimately establish malignancies. The concept of immunotherapy was formulated, as narrated in “A Cure Within”⁵. As early as the 1890s, surgeon William Coley observed that tumors could autonomously regress after severe bacterial infections. His subsequent development of “Coley’s Toxins” marked one of the first attempts at cancer immunotherapy. Understandably, largely ineffective, these efforts nevertheless opened up the path that the immune system could be harnessed to effectively fight cancer. In 1957, Burnet and Thomas proposed the “immune surveillance theory”, suggesting a theoretical framework for the body to harness the immune system to guard against tumors, marking the official recognition of immunotherapy as an anti-cancer weapon. The 1980s heralded the dawn of clinical translation: Steve Rosenberg achieved breakthroughs in advanced cancer treatments using lymphokine-activated killer cells. This procedure involved removal of lymphocytes from the patient’s blood for activation by IL2 and re-infusing them back into the patient. This was a first attempt to empower the immune system to eliminate tumors. In 1986, the FDA approval of human alpha interferon for hairy cell leukemias marked the official recognition of immunotherapy as a viable anti-cancer treatment. Though the first-generation CAR-T therapy, reported in 1987, failed to meet efficacy expectations, it quietly opened the door to the era of precision cellular immunotherapy.

The landscape of immuno-oncology underwent a transformation with the advent of immune checkpoint blockade, beginning with the FDA approval of ipilimumab (anti-CTLA-4) in 2011 for metastatic melanoma, followed by the PD-1 inhibitors nivolumab and pembrolizumab. These drugs, which “release immune brakes”, led to unprecedented long-term survival in a subset of patients with advanced cancers. However, a critical challenge remains: the lack of clarity in identifying optimal patient populations for immunotherapy. For instance, ipilimumab demonstrates objective response rates of only 10–15% in melanoma patients⁶, while PD-1 inhibitors achieve response rates ranging from approximately 15–20% in unselected cancer populations⁷. Although combination therapies, such as chemotherapy or targeted therapy with PD-1 inhibitors, have been developed to improve clinical efficacy, they also come with increased clinical toxicities and potential risks that may outweigh the benefits⁸. This is particularly true for hepatocellular carcinoma (HCC), where treatments such as anti-PD-1 antibodies have shown limited efficacy. In cases of non-alcoholic steatohepatitis (NASH)-induced HCC, due to the presence of immunosuppressive microenvironments (such as the enrichment of regulatory T cells), these antibodies may instead even promote cancer progression⁹. Furthermore, the effectiveness of conventional therapeutic modalities — including transarterial chemoembolization, selective internal radiation therapy, and systemic chemotherapy — offers modest benefits while inflicting substantial collateral damage to non-malignant hepatocytes and further compromising immune function¹⁰. To this end, targeted therapies, including multi-kinase inhibitors such as sorafenib and lenvatinib, are more precise than traditional chemotherapies; however, their success is undermined by the extreme heterogeneity of HCC and the development of resistance¹⁰. Consequently, the goal of achieving enduring control in cancers like HCC remains largely elusive. Current immunotherapies may preserve some immune cells but fail to address the fundamental problem when the cancer tissues create an environment inaccessible to immune cells, effectively protecting the cancer mass from the body’s immune system. Therefore, effective cancer treatment by immunotherapy must prioritize remobilizing the intrinsic immune system to overcome the protective para-tumor environment.

The landmark discovery of Lin and his team in Cell Research¹¹ meets this demand, presenting a paradigm shift in cancer therapy centered on the use of a glucose starvation mimetic named aldometanib¹² to treat cancer as a metabolic chronicity¹¹. Mechanistically, aldometanib activates AMP-activated protein kinase (AMPK) and inhibits mTORC1 through the above-mentioned glucose-sensing pathway¹². It prevents the lysosomal-localized pool of aldolase from binding to its substrate, fructose-1,6-bisphosphate, thus generating a pseudo-starvation for glucose to trigger the activation of the lysosomal pool of AMPK¹². Crucially, this AMPK activator directly addresses the above-mentioned clinical bottlenecks: it can revert the tumor microenvironment while demonstrating undetectable toxicity in animal models, thereby offering a potential solution to the toxicity–efficacy dilemma that plagues current combination therapies. The key message is that cancer elimination should not just rely on direct cytotoxicity of the drug, nor on the direct activation of the immune cells, but on its ability to clear the “roadblocks” that had prevented the internal immune cells from attacking the tumor. Remarkably, treatment with aldometanib significantly inhibited HCC growth in multiple mouse models that represent various etiologies of HCC, including DEN-HFD HCC (representing NASH-HCC), MYC;Trp53^–/– HCC (with MYC and TP53 being two of the most frequently altered genes in HCC patients), and various orthotopic HCC allografts. To top it off, treatment with aldometanib enables hepatoma-bearing mice to survive to a ripe old age¹¹. A critical insight from the study is that this effect appears to rely largely on the internal immune system, as aldometanib shows no efficacy in immunodeficient mice. The most dramatic outcome was the substantial infiltration of CD8⁺ T lymphocyte cells into the tumors in the aldometanib-treated mice¹¹. Further analyses on the buildup of the immune system in the HCC-bearing mice showed that CD8⁺ T cells were intact. Another surprise the authors found was that the antitumor effect of aldometanib requires AMPK activation specifically in the non-cancerous, para-tumor host liver tissue¹¹. It is reasonable to suggest that aldometanib-induced AMPK activation rebalances the metabolic landscape of the non-cancerous para-tumor tissues through the lysosomal aldolase–AMPK complex, the “master controller” of innate wellness, allowing for the infiltration of CD8⁺ T cells by increased levels of granzyme B and IFNγ to become cytotoxic/tumoricidal. As such, depletion of CD8⁺ T cells eliminated the therapeutic benefit, confirming the crucial anti-tumor role of aldometanib¹¹. Additionally, aldometanib reduced the populations of immune-suppressive cells such as neutrophils and tumor-associated macrophages, effectively dismantling major barriers within the tumor and non-tumor tissues. Importantly, the authors combined aldometanib and immunotherapeutic antibodies, showing that aldometanib significantly enhanced the efficacy of HCC to anti-PD-1 treatment, suggesting a strong potential for combinational treatments¹¹.

Together, Lin et al. provided compelling evidence that targeted metabolic intervention can overcome immunosuppressive barriers, at least as demonstrated in the model system of HCCs. By activating AMPK in the host tissue, aldometanib “clears the roads”, allowing the body’s own immune system to traffic effectively, infiltrate tumors, and execute its tumoricidal functions (Fig. 1). If proven in humans, this discovery provides the first critical evidence for a key role that metabolism plays in immunotherapy that Lin defined as “Metaboimmunotherapy”. The tumor-suppressive role of aldometanib shifts the focus away from the killing of cancer cells to the reconstruction of the endogenous environment around the tumor cells for the immunocompetent cells to mobilize and surround the cancer cells, containing their proliferation without the severe cytotoxicity encountered in most, if not all, known cancer therapies. It is no longer about saving the patients by killing their cancer cells but about curing cancer from the metabolic angle by mimetic of starvation occurring during fasting hours or combined with another immunotherapeutic. It also allows cancer patients to co-exist with cancer by converting a life-threatening disease into a life-long, manageable chronic disease, enabling them to live with cancer in good health to a ripe old age.

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The Author(s) 2026. Published by Higher Education Press. This is an Open Access article distributed under the terms of the CC BY license (https://creativecommons.org/licenses/by/4.0/).

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Tan, C., Ellisman, M., Hill, C., Wei, W., Kates, J. Metaboimmunotherapy: a revolutionary concept of living with cancer Vita https://doi.org/10.15302/vita.2026.01.0004 ()