Author: José R. Pineda got his Ph.D. from University of Barcelona in 2006. Since 2007 he has worked for Institut Curie and The French Alternative Energies and Atomic Energy Commission. Currently he is a researcher of the EHU. He investigates the role of stem cells in physiologic and pathologic conditions.

For decades, Alzheimer’s research has been dominated by a seemingly intuitive idea: the disease is largely explained by the accumulation of abnormal proteins in the brain, primarily beta-amyloid and tau. However, while this view has been useful, it has fallen short in explaining certain fundamental aspects. One of the most striking is that Alzheimer’s affects women far more than men. This is not a minor difference: roughly two-thirds of cases occur in women, and the clinical progression tends to be faster and more severe. The work by López-López and colleagues addresses this imbalance from a different angle. Instead of focusing exclusively on protein accumulation, it shifts attention to the brain’s immune system—specifically to a molecular pathway known as interferon signaling. What the study proposes is that the brain’s immune response, far from being a mere bystander, could be a central driver of the disease, and one that operates differently in men and women ¹.

To understand the importance of this idea, it helps to briefly consider what interferons are. They are molecules that form part of the body’s first line of defense against infections, especially viruses. They activate genetic programs that help cells detect and neutralize threats. Under normal conditions, this system is essential for survival. The problem arises when it becomes chronically or inappropriately activated, as is the case in several inflammatory diseases ². So, the study begins with an analysis of human brain tissue from Alzheimer’s patients. Using transcriptomics (techniques that measure the activity of thousands of genes at once) the authors identified a clear pattern: in the brains of women with Alzheimer’s, genes associated with the interferon response were much more strongly activated than in men (Figure 1). This pattern was not explained by differences in disease severity, since both groups showed comparable levels of neuropathological damage. Instead, it points to an intrinsic difference in how the brain responds to the disease. This finding is significant because it suggests that women not only develop Alzheimer’s more often, but may do so through a partially distinct biological pathway. In other words, the same clinical diagnosis may conceal different underlying mechanisms depending on sex.

To move beyond correlation and explore causality, the researchers turned to animal models. They used genetically modified mice (APP/PS1), widely employed in Alzheimer’s research because they develop amyloid plaques similar to those seen in patients. Once again, the same pattern emerged: female mice showed much stronger activation of the interferon pathway, along with increased brain inflammation, neuronal damage, and functional impairment. An especially interesting point is that these differences were not limited to amyloid plaque levels. Indeed, female mice did have more plaques, but the study shows that neuronal damage and inflammation cannot be explained solely by amyloid accumulation. This supports a growing idea in the field: that Alzheimer’s toxicity depends not only on protein buildup, but also on how the brain responds to it. In this context, microglia (the brain’s resident immune cells) become key players. Cell-level analyses revealed that these cells are the main drivers of interferon activation. In essence, microglia detect signals of damage or stress and launch an inflammatory response which, if sustained over time, can ultimately harm neuronal tissue. To test whether this pathway is not only associated with disease but actually contributes to it, the authors performed direct manipulation experiments acutely activating interferon signaling in healthy animals using an immune stimulus. To do that, they did intraperitoneal administration of polyinosinic:polycytidylic acid (poly(I:C)) to induce inflammation, but also they performed crossings between the APP/PS1 mice and a microglia-specific Rela conditional knockout line (AD hiIFN). The result was striking: within hours to days, the brains of these animals began to show changes resembling Alzheimer’s pathology, including altered neuronal activity, synaptic disruption, and markers of axonal damage. This results suggest that activation of this pathway is not a secondary phenomenon, but may be sufficient to induce key features of the disease. In parallel, the researchers performed the inverse experiment: they chronically enhanced interferon signaling in microglia within APP/PS1 mice (an Alzheimer’s disease model). This led to a worsening of neurodegenerative features, even though, paradoxically, amyloid plaque levels did not increase—and in some cases even decreased. This last finding is particularly revealing because it challenges a widespread assumption: that fewer plaques necessarily means a healthier brain. Here, the opposite happens!! The animals had less amyloid burden, yet more neuronal damage and worse function. This points to inflammation, and specifically interferon signaling, as an independent driver of degeneration.

Next, the key question is whether this pathway can be targeted therapeutically. To address this, the study explores a pharmacological intervention aimed at the cGAS–STING pathway (a molecular system that senses cellular damage and triggers interferon production). Using a specific inhibitor (STING inhibitor C-176), the researchers demonstrated by RNA-seq and immunohistochemistry that the treatment was able to reduce interferon signaling in the brain. The results were consistent: inflammation decreased, neuronal integrity was better preserved, and cognitive performance improved in memory tests (very important from the therapeutic and functional perspective). More importantly, these effects were far more pronounced in females, which aligns with the idea that this pathway is more active in them and therefore more impactful when blocked. Notably, these improvements occurred without significant changes in amyloid plaque levels. Once again, the conclusion is clear: modulating the immune response may be as important as, or even more important than, targeting protein aggregates. Taken together, this work proposes a shift in how Alzheimer’s is understood. Rather than viewing it solely as a disease of protein accumulation, it suggests it is also—critically—a disorder of immune dysregulation. More specifically, one in which excessive interferon signaling plays a central role, particularly in women.

The practical implications are twofold. First, it opens the door to therapies that modulate immune pathways in the brain, something already feasible in other diseases using drugs that target similar mechanisms. Second, it highlights the importance of incorporating sex as a biological variable in both research and treatment design. What works in men may not work the same way in women, and vice versa. As with any preclinical study conducted in mice we must be cautious when extrapolating to humans: results in animal models do not always translate directly, and manipulating the immune system carries inherent risks, given its essential role in protecting against infections. However, the value of this work lies not only in its potential clinical applications, but in the conceptual framework it offers.

By identifying interferon signaling as a key factor in sex-specific vulnerability to Alzheimer’s, the study provides a mechanistic explanation for a long-observed but poorly understood phenomenon. Perhaps more importantly, it suggests that intervening in this pathway could alter disease progression even without changing classical amyloid pathology. In a field where many clinical trials have failed by focusing solely on plaque removal, this perspective is not just novel, it may be necessary to explore it in the future.

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What if we could stop blood cancers before they even start? New research reveals ¹ that chronic inflammation dramatically reshapes the bone marrow environment years before leukemia emerges, potentially offering a window for early intervention.

The Hidden Life of the Bone Marrow

Every second, your bone marrow produces millions of new blood and immune cells through delicate cooperation between blood stem cells and supportive stromal cells. Over time, aging, inflammation, or genetic mutations can disrupt this partnership, allowing mutated stem cells to silently expand.

This leads to a condition called clonal hematopoiesis, or CHIP, which affects roughly 10–20% of adults over 60 years old. Despite the lack of symptoms, the condition increases blood cancer risk tenfold and doubles the risk of cardiovascular disease. In some cases, it can progress to myelodysplastic syndrome, where bone marrow fails to produce healthy blood cells, and up to 30% of these advance to acute myeloid leukemia—an aggressive and often fatal blood cancer.

Uncovering the Culprit: Inflammation

Researchers conducted an in-depth molecular analysis of human bone marrow samples from healthy donors, people with CHIP, and patients with myelodysplastic syndrome (leukaemia). Using advanced techniques including single-cell sequencing and biopsy imaging, they built a high-resolution map of the bone marrow environment across these different stages.

The results revealed a striking cellular transformation beginning well before clinical disease appears. Researchers identified inflammatory stromal cells instead of normal stem-cell-supporting cells. Unlike healthy stromal cells, these inflammatory cells release signaling molecules that attract and activate certain immune cells (T cells). In turn, these T cells amplify the inflammatory signal, creating a self-reinforcing loop that sustains chronic inflammation, suppresses healthy blood formation, and promotes abnormal blood vessel development.

Surprisingly, the mutated blood cells do not directly drive inflammation. Instead, the inflammatory network in the surrounding microenvironment becomes dominant, replacing much of the bone marrow’s regenerative structure. As diseased stem cells also fail to trigger production of important signaling molecules, this could explain why bone marrow function deteriorates.

This discovery indicates inflammation has a central force in early blood disease stages and establishes the bone marrow microenvironment as a critical therapeutic target. Based on these findings, anti-inflammatory treatments may help preserve bone marrow function in older adults with CHIP. In addition, the distinct molecular signatures of these inflammatory cells may serve as biomarkers to identify at-risk individuals long before clinical symptoms emerge, possibly preventing progression to leukemia.

What I find particularly interesting about the research is that it shows yet another example of how deadly chronic infammation can be. I would not be surprised if the incidence of this disease were to increase in the next years, as we are most living under chronic stress conditions, which is one of the biggest contributors to chronic inflammation. To me, this is more of a health issue, it is a social issue and to get rid of it, we need much more than antiinflammatory drugs.

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Author: Marta Irigoyen is a postdoctoral researcher at CIC bioGUNE

Chimeric antigen-specific receptor (CAR) T-cell immunotherapy targeting B-cell maturation antigen (BCMA; BCMA-CAR T cells) has produced remarkable clinical responses in advanced multiple myeloma (MM), with a substantial fraction of patients achieving complete remission ¹. However, many patients relapse within months, largely due to insufficient CAR T-cell persistence, a recognized mechanism of acquired resistance ². A major barrier to durable responses is the tumor microenvironment (TME), which is profoundly reshaped by tumor metabolic reprogramming ³. In fact, many tumor types, specially MM, are highly dependent on glutamine (Gln) metabolism for cell survival and proliferation ⁴. Thus, Gln “addiction” depletes local Gln levels and availability, impairing antitumor T-cell effector functions and promoting immune escape.

Based on these observations, a team of researchers hypothesized ⁵ that Gln deprivation within the TME limits the efficacy of CAR T-cell therapies. Indeed, antigen-specific T cells fail to proliferate and to produce interferon gamma (IFN-γ) under Gln-restricted conditions. They therefore investigated whether enhancing Gln uptake via overexpression of the Human SLC1A5 (ASCT2) amino acid transporter could improve the metabolic fitness and the antitumor activity of BMCA-CAR T cells in MM.

To assess the functional impact of ASCT2 overexpression in T cells, the authors infected CD8⁺ and CD4⁺ T cells from mice with an expression vector containing Asct2. To assess the impact of enhanced Gln uptake on T-cell function, CD4⁺ and CD8⁺ T cells from mouse spleens were stimulated with anti-CD3/CD28 beads at varying Gln concentrations. Interestingly, Asct2 overexpression significantly improved T-cell proliferation and IFN-γ production. Similar enhancements were observed in CD8⁺ OT-I (these cells contained a transgenic TCR designed to recognize ovalbumin (OVA) peptide 257-264 on MHC class I, modeling thus cytotoxic T-cell responses) and CD4⁺ OT-II T cells (these cells contained a transgenic TCR designed to recognize OVA peptide 323-339 on MHC class II, modeling the helper T-cell responses). Thus, Asct2-overexpressing OT-I T cells showed increased cytotoxicity against B16OVA cells. B16OVA cells are a well established in vitro model for cancer immunotherapy, expressing ovalbumin in order to facilitate strong immune responses to tumor antigens. The authors found that, even at low Gln levels, Asct2-overexpressing CD4⁺ OT-II T cells were more efficient lysing B16OVA cells.

Next, to assess the potential of Asct2 overexpression to enhance ACT therapy in vivo, B16OVA tumor-bearing mice were treated with either control or Asct2 CD8⁺ OT-I T cells. Interestingly, 14 days after tumor injection they found lower levels of Gln in the interstitial fluid, confirming a Gln-deficient TME. Then, mice were subcutaneously injected with B16OVA cells and, 7 days later, treated with control or Asct2 CD8+ OT-I T cells. Remarkably, mice treated with Asct2 CD8⁺ OT-I T cells exhibited a delay in tumor growth as evidenced by tumor weight and survival rate analysis. Moreover, mice treated with Asct2 CD8+ OT-I T cells showed a higher number of IFN-γ–producing antigen-specific T cells in the spleen compared with control T cells.

Given the well-established Gln “addiction” of MM ⁶ and the consequent Gln depletion in the bone marrow (BM), the authors next evaluated whether Asct2 overexpression in BCMA-CAR T cells could improve Gln uptake and potentially benefit CAR T-cell immunotherapy in MM. Because MM expresses BCMA, they generated a murine anti–Bcma-CAR T-cell therapy effective against MM in vivo. They tested whether Asct2 overexpression could improve their efficacy in vivo and observed that Bcma-CAR cells exhibited robust proliferation and high IFN-γ secretion when stimulated with Bcma. Besides, subsequent co-culture experiments with Bcma-expressing MM cells confirmed that Bcma-CAR T cells selectively secreted IFN-γ, and displayed cytolytic activity against MM cells. Replacement of the GFP reporter with ASCT2 yielded BCMA-CAR/ASCT2 T cells with enhanced Gln transport capacity. In coculture assays, ASCT2-expressing BCMA-CAR T cells exhibited superior cytolytic activity against MM cells, particularly under low-Gln conditions.

To evaluate if Asct2 overexpression could enhance ACT immunotherapy with Bcma-CAR T cells in vivo, they used a murine model in which mice were challenged with MM cells and treated IV with CD8⁺ and CD4⁺Bcma-CAR T cells (1:1 ratio) or Asct2 Bcma-CAR T cells. Interestingly, Asct2 Bcma-CAR T cells significantly improved overall survival (OS) in mice challenged with tumors, achieving 90% survival at day 100 after treatment. Besides, fourteen days after CAR T-cell transfer, there was a significant reduction in tumor cells in the BM of both CAR T-cell–treated mice groups, being more significant in the BM of mice treated with Asct2 Bcma-CAR T cells compared with those treated with Bcma-CAR T cells. Moreover, there was a higher number of infiltrating CAR T cells in both the spleen and BM of mice receiving Asct2 Bcma-CAR T cells. Then, they next evaluated the antitumor effect of the Bcma-CAR T cells in a genetic MM preclinical model that closely mimics common genetic alterations observed in human MM and, similarly, treatment with Asct2 Bcma-CAR T cells significantly enhanced OS compared with conventional Bcma-CAR T cells.

Finally, the authors explored the clinical relevance of ASCT2 expression in MM. RNA-seq analysis of BM aspirates of untreated patients with MM compared ASCT2 expression levels in various B-cell subtypes obtained from healthy donors as previously described, showed a marked upregulation in MM cells compared with normal B-cell subsets, suggesting a potential prognostic relevance of ASCT2 expression in MM. Next, to explore the clinical relevance of ASCT2 overexpression in human CAR T cells, they created 2 lentiviral constructs encoding an antihuman BCMA-CAR. They prepared a conventional BCMA-CAR and the ASCT2 BCMA-CAR construct coexpressing ASCT2. Notably, ASCT2 BCMA-CAR T cells showed greater proliferation and higher IFN-γ production upon BCMA stimulation at various Gln concentrations, and they had a higher proportion of naïve stem cell memory and central memory subsets. To further demonstrate the importance of ASCT2, they performed cytotoxicity assays with BCMA-CAR T cells against tumor cells with different ASCT2 levels. Silencing ASCT2 in MM cells reduced Gln uptake and confirmed the functional importance of this transporter in tumor–immune metabolic competition.

In summary, Asct2 overexpression enhances T-cell and CAR T-cells metabolic fitness and effector function under Gln-restricted conditions. In both B16OVA melanoma and MM in vivo tumor models, this strategy improved antitumor immunity and increased overall survival. These findings support metabolic engineering of CAR T cells as a rational approach to overcome nutrient deprivation in the TME an to enhance durable tumor control.

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