Macrophages are highly adaptable cells. Rather than existing in a single fixed state, they respond continuously to signals from damaged tissue, cancer cells, cytokines, metabolites and neighboring immune cells. In simplified laboratory terminology, macrophages with an M1-like profile are associated with inflammatory and antimicrobial activity, whereas M2-like macrophages are often linked to tissue repair, immune suppression and tumor progression. In real tumors, macrophage states form a spectrum rather than two sharply separated categories. Nevertheless, the balance between inflammatory and immunosuppressive functions can strongly influence the outcome of cancer. TAMs that suppress immune responses may protect malignant cells from attack, stimulate blood-vessel formation and assist invasion into surrounding tissues. Reprogramming these cells has therefore become an important objective in cancer immunotherapy.

The new work focuses on Gsα, the alpha subunit of the stimulatory heterotrimeric G protein. This molecule is best known as a component of signaling downstream from G protein-coupled receptors, a vast family of cell-surface receptors that detect hormones, neurotransmitters, lipids and other extracellular signals. When activated, Gsα commonly stimulates adenylyl cyclase, increasing intracellular cyclic AMP and activating downstream effectors such as protein kinase A. However, G protein signaling is not confined to a single linear route. Depending on the receptor, cellular context and regulatory proteins present, Gsα-associated signals can influence several networks, including the mitogen-activated protein kinase pathway. MAPK signaling includes interconnected kinase cascades such as ERK, p38 and JNK, which regulate gene expression, differentiation, stress responses and inflammatory behavior.

To investigate the role of Gsα in macrophages, the researchers used mice in which the protein was selectively removed from these immune cells. These animals, referred to as GsαMKO mice, were compared with control mice carrying the intact Gsα gene. The team examined tumor development using two widely used experimental systems: B16 melanoma cells and MC38 colorectal cancer cells. In both models, the absence of macrophage Gsα was associated with faster tumor growth. Experiments involving metastatic B16 disease also indicated a greater burden of cancer spread in mice lacking Gsα in macrophages. These findings suggest that the protein affects more than the size of the primary tumor; it may also influence the ability of the tumor microenvironment to support dissemination and colonization of distant organs.

The researchers then examined the molecular identity and behavior of macrophages inside the tumors. Macrophages containing Gsα showed increased expression of CD86, CCR5, Il1b and Nos2, genes and proteins commonly associated with inflammatory activation and immune stimulation. CD86 can provide important co-stimulatory signals during interactions between antigen-presenting cells and T cells. CCR5 is a chemokine receptor involved in immune-cell trafficking, while Il1b encodes interleukin-1 beta, a potent inflammatory mediator. Nos2, also known as inducible nitric oxide synthase, enables macrophages to produce nitric oxide, a reactive molecule involved in antimicrobial and immune effector functions. In contrast, Gsα activity was associated with lower levels of CD206 and Il10, markers linked in this context to alternative, immunosuppressive macrophage behavior.

These changes were not merely molecular labels. The study indicates that Gsα-positive macrophages were better able to contribute to antitumor immunity. Their altered chemokine-receptor profile could affect how macrophages are recruited and positioned within tumors, while their inflammatory gene program could improve their ability to oppose malignant cells. The researchers also observed increased effector activity among CD8-positive T cells in tumors from control animals compared with animals lacking macrophage Gsα. CD8-positive T cells are cytotoxic lymphocytes capable of recognizing and killing abnormal cells, but their effectiveness can be weakened by suppressive conditions within the tumor microenvironment. The results suggest that macrophage Gsα may indirectly strengthen T-cell responses by making the surrounding immune environment less tolerant of cancer.

At the mechanistic level, the investigators linked this macrophage reprogramming to MAPK activity. They reported that Gsα promoted phosphorylation of ERK, p38 and JNK—chemical modifications that activate these kinases and allow them to transmit signals toward the nucleus and other cellular targets. Once activated, MAPK pathways can alter transcription factors and inflammatory gene networks, changing how macrophages respond to tumor-derived signals. The simultaneous involvement of ERK, p38 and JNK is notable because these branches can control overlapping yet distinct aspects of macrophage biology. ERK often participates in proliferation and differentiation signals, p38 is strongly associated with stress and inflammatory responses, and JNK can regulate cytokine production, apoptosis and transcriptional remodeling. Together, their activation may help maintain the proinflammatory state observed in macrophages containing Gsα.

Additional cell-based experiments supported the conclusion that the effect was intrinsic to macrophages rather than simply a consequence of unrelated differences between the animals. Bone marrow-derived macrophages from Gsα-deficient mice displayed altered activation patterns, and restoring exogenous Gsα changed the molecular profile of these cells. The study also used tumor-conditioned media, which contains soluble factors released by cancer cells, to model some of the signals macrophages encounter in the tumor microenvironment. These experiments point to a system in which cancer-derived signals can push macrophages toward tumor-supporting behavior when Gsα is absent, whereas Gsα helps preserve or restore inflammatory functions. The investigators further reported increased CD31 expression in tumors from GsαMKO mice, consistent with enhanced vascular features that could facilitate tumor expansion and metastatic escape, although the precise relationship between macrophage Gsα and blood-vessel formation requires further study.

The findings are especially relevant because many current cancer treatments focus primarily on malignant cells or on immune checkpoints, such as the PD-1 and PD-L1 pathway. Checkpoint inhibitors can release T cells from inhibitory signals, but their success depends on the broader immune environment. Immunosuppressive TAMs are one reason tumors may remain resistant even when cytotoxic lymphocytes are present. A therapy designed to preserve Gsα activity in macrophages, enhance its downstream signaling or selectively activate the relevant MAPK branches could theoretically complement existing immunotherapies. However, the study does not establish a treatment for patients, and directly manipulating G protein signaling would carry substantial risks. Gsα operates in many tissues and participates in physiological processes ranging from hormone responses to metabolism, so a systemic drug could produce effects far beyond the tumor. Any future strategy would need to target macrophages with high precision and determine which receptors or intracellular intermediates connect Gsα to ERK, p38 and JNK in different cancers.

The authors emphasize that their conclusions arise from B16 and MC38 mouse models and from experimental macrophage systems. Human tumors contain diverse macrophage populations shaped by genetics, treatment history, tissue origin and metabolic conditions, and these cells may not respond identically to Gsα manipulation. The study also highlights an important complexity in cell signaling: the same molecular pathway can have different consequences depending on the cell type and biological setting. While Gsα-associated cyclic AMP signaling has been linked in other contexts to anti-inflammatory or M2-like macrophage behavior, this work identifies a macrophage-specific role in which Gsα supports inflammatory antitumor activity through MAPK phosphorylation. Further research will be needed to validate Gsα expression and MAPK activity in human TAMs, establish whether the relationship predicts patient outcomes and determine whether selectively reprogramming this pathway can improve responses to immunotherapy without provoking harmful inflammation. For now, the study adds Gsα to the growing list of molecular switches that may decide whether the immune cells surrounding a tumor become its allies—or its enemies.

Subject of Research: Gsα signaling in tumor-associated macrophages and its influence on tumor growth, metastasis and antitumor immunity

Article Title: Gsα deficiency in macrophages promotes tumor progression via the MAPK signaling pathway

Article References: Yan W, Yang J, Tan S, et al. “Gsα deficiency in macrophages promotes tumor progression via the MAPK signaling pathway.” Journal of Molecular Medicine 104, article 52 (2026).

Image Credits: AI Generated

DOI: 10.1007/s00109-026-02660-2

Keywords: Gsα, tumor-associated macrophages, TAMs, macrophage polarization, MAPK signaling, ERK, p38, JNK, cancer immunotherapy, tumor progression, metastasis

NTM infections are becoming an increasingly important global health problem. The organisms are found widely in soil and water and can cause serious, persistent lung disease, particularly in people with bronchiectasis, chronic obstructive pulmonary disease, cystic fibrosis or other underlying respiratory conditions. The Mycobacterium avium complex is among the most common causes of NTM pulmonary infection. Treatment typically involves several antibiotics taken for many months, yet even when bacterial numbers are reduced, patients may continue to experience coughing, fatigue, breathlessness and progressive lung damage associated with chronic inflammation.

Corticosteroids have traditionally been used cautiously during mycobacterial infections because they suppress immune activity. The concern is that dampening T-cell or innate immune responses could allow bacteria to multiply more rapidly. The new study addresses a central question in NTM treatment: whether it is possible to reduce excessive inflammation without eliminating the immune mechanisms that help contain the infection.

The Trinity research team examined the response of primary human macrophages to M. avium. Macrophages are immune cells that engulf microbes and coordinate early antimicrobial defence. Once infected, they undergo major functional and metabolic changes. These include increased glycolysis, a process in which cells rapidly convert glucose into energy and metabolic intermediates. Although glycolysis can support immune activation, an excessive or prolonged metabolic shift may also drive the production of inflammatory molecules that contribute to tissue injury.

Using real-time metabolic measurements, the researchers observed that M. avium infection increased macrophage metabolic activity. Dexamethasone significantly reduced this infection-associated metabolic response. The steroid also lowered the production of several inflammatory cytokines and chemokines, including tumour necrosis factor, interleukin-1 beta, interleukin-6 and interleukin-8. These signalling proteins recruit and activate additional immune cells, but sustained production can intensify inflammation in infected tissues.

The key result was that the reduction in inflammatory activity did not appear to come at the cost of bacterial control. Macrophages treated with dexamethasone did not show increased growth of M. avium compared with untreated infected cells. In other words, the steroid separated two responses that are often assumed to be inseparable: the inflammatory reaction and the cell’s ability to restrict intracellular bacteria. This distinction is important because inflammation is not always equivalent to effective antimicrobial protection.

The findings build on earlier work from the same research group involving Mycobacterium tuberculosis. In that setting, the researchers showed that dexamethasone could alter the metabolism of infected macrophages. The new results indicate that related metabolic pathways may also shape the immune response to NTM, although the biological behaviour of NTM species differs from that of the tuberculosis bacterium. The work further supports the idea that metabolic changes in myeloid cells can influence inflammation without necessarily determining whether bacteria are controlled.

“Our study suggests that it may be possible to fine-tune this response by reducing damaging inflammation while still preserving the immune defences that help control infection,” said Dr Donal Cox, senior author and a researcher at the Trinity Translational Medicine Institute. The study’s results, he added, provide a rationale for examining corticosteroids as potential host-directed therapies rather than using them solely for their conventional anti-inflammatory effects.

Professor Joseph Keane, Professor of Medicine at Trinity, said the research demonstrated a central role for glycolysis in the macrophage response to NTM. The metabolic shift was sufficient to accompany the inflammatory response, but it was not necessary for the macrophages’ antimicrobial activity. This suggests that the pathways producing inflammation and those responsible for bacterial restriction may be selectively targeted, at least in human cells grown under laboratory conditions.

The researchers emphasise that the study does not establish dexamethasone as a treatment for patients with NTM disease. The experiments were performed using primary human macrophages rather than whole organisms or clinical trial participants. Corticosteroids can have broad effects on immunity and, depending on dose, duration and the patient’s underlying condition, may increase susceptibility to other infections or produce significant side effects. Animal studies and carefully designed clinical investigations will therefore be needed to determine whether dexamethasone can safely improve symptoms or limit tissue damage when combined with standard antimicrobial therapy. Nevertheless, the results offer a potential new strategy for NTM disease: treating the host’s harmful inflammatory response while preserving the immune functions required to keep the bacteria under control.

Subject of Research: Dexamethasone, macrophage metabolism, inflammation and host-directed treatment of Mycobacterium avium and nontuberculous mycobacterial disease.

Web References: https://doi.org/10.1093/infdis/jiag394

References: Journal of Infectious Diseases, DOI: 10.1093/infdis/jiag394

Keywords: Nontuberculous mycobacteria, Mycobacterium avium, dexamethasone, corticosteroids, macrophages, glycolysis, immunometabolism, inflammatory cytokines, host-directed therapy, respiratory disease

Melanoma is the fifth most common cancer in the United Kingdom and one of the most dangerous forms of skin cancer when it spreads beyond the skin. Surgery can be curative when the disease is detected early, while advanced melanoma may be treated with targeted drugs or immunotherapy. Checkpoint inhibitors have transformed care by releasing molecular brakes that normally restrain T cells, allowing these immune cells to recognise and attack tumour cells. Yet the treatment is far from universally effective: nearly half of patients do not obtain meaningful benefit, while some develop serious inflammatory side effects as the immune system attacks healthy tissues.

The new study focused on the adaptive immune system, the branch of immunity that develops highly specific responses to foreign or abnormal targets. T cells can directly kill cancer cells or coordinate broader immune activity, while B cells produce antibodies and can also present tumour-related antigens to T cells. Although B cells have historically received less attention in cancer immunology than T cells, growing evidence suggests that they can influence whether immunotherapy succeeds. The King’s-led team examined both cell types together, tracking how their activation states changed during treatment.

Researchers analysed blood samples from 24 people with stage 2 to stage 4 melanoma who were receiving checkpoint inhibitor immunotherapy at Guy’s and St Thomas’ NHS Foundation Trust. Samples were collected before treatment and at two time points during therapy, including within the first six weeks. Blood from 25 healthy volunteers was also assessed for comparison. Instead of examining only broad cell categories, the scientists used mass cytometry, a highly multiplexed technology that measures numerous proteins and other characteristics on individual cells simultaneously.

Mass cytometry enabled the team to distinguish rare immune-cell populations that would be difficult to identify using conventional methods. The researchers could determine whether B and T cells displayed signs of activation, maturation, proliferation or impaired function, then follow those features over time. This approach revealed substantial variation between patients even before treatment began, suggesting that the immune system’s starting condition may influence how an individual responds to immunotherapy.

Patients with favourable outcomes tended to show renewed activation and expansion of both B-cell and T-cell populations during the early stages of treatment. This pattern was interpreted as evidence of immune reinvigoration: checkpoint inhibitors appeared to restore or amplify immune responses that had been suppressed by the tumour or by chronic exposure to tumour antigens. The coordinated behaviour of the two cell types was particularly important, because effective anti-cancer immunity often depends on communication between antibody-producing B cells, antigen-presenting cells and tumour-killing T cells.

In contrast, patients whose blood continued to contain immature or poorly functioning B-cell populations during treatment generally experienced less favourable outcomes. Weaker baseline B-cell and T-cell anti-cancer responses were also associated with poorer survival after therapy. Certain T-cell subtypes appeared to be linked with treatment-related toxicity, indicating that the same immune activation that can damage tumours may sometimes trigger inflammation in healthy organs. However, the researchers emphasised associations rather than definitive proof that these cell populations directly cause treatment success or side effects.

The results are promising because blood sampling is substantially less invasive than repeated tumour biopsies. A future immune-monitoring test could potentially measure B-cell maturation, T-cell activation and changes in immune-cell abundance before and shortly after therapy begins. Such information might help oncologists decide which patients should continue a treatment, receive intensified surveillance or be assessed early for immune-related complications. Nevertheless, the study was small, and the findings must be validated in larger patient groups before they can be used to guide clinical decisions. Immune profiles may also differ between cancer types, treatment combinations and disease stages.

Lead author Lucy Booth, a PhD student at King’s College London’s St John’s Institute of Dermatology, said the work highlights the importance of studying B cells alongside T cells. Professor Sophia Karagiannis, Professor of Translational Cancer Immunology and Immunotherapy at King’s, said that analysing the two adaptive immune-cell populations over time showed how they simultaneously change during treatment. The group previously identified blood-based B-cell markers associated with immunotherapy toxicity and treatment response, and now plans to investigate how B and T cells behave inside tumours themselves. The researchers also hope to repeat the analysis in larger cohorts and in other cancers, including triple-negative breast cancer, where treatment options remain limited.

Subject of Research: People

Article Title: Circulating B cell and T cell activation states predict clinical outcomes in melanoma and reveal dynamic immune reinvigoration with checkpoint inhibitor immunotherapy

Web References: Journal for ImmunoTherapy of Cancer study; King’s College London research background

References: DOI: 10.1136/jitc-2026-015585

Keywords: melanoma, immunotherapy, checkpoint inhibitors, B cells, T cells, immune profiling, mass cytometry, cancer immunology, treatment response, immune-related side effects

The mechanism through which pomalidomide operates has garnered considerable attention in the context of multiple myeloma. Conventional treatments, while beneficial, often fail to sustain long-term remission due to the disease’s inherent aggressiveness. Clinical studies highlighted in the editorial indicate that the addition of pomalidomide to treatment plans featuring standard options like bortezomib and dexamethasone significantly boosts patients’ immune responses. The enhancement of T cells and natural killer (NK) cells, integral components of the immune system, is particularly critical, as these cells play pivotal roles in identifying and eradicating malignancies.

As researchers delve deeper into the biological underpinnings of pomalidomide’s efficacy, it becomes apparent that the drug targets Cereblon, a crucial component of the CRL4 E3 ubiquitin ligase complex. This interaction leads to the degradation of Ikaros and Aiolos, proteins that repress T cell activity. Consequently, by dismantling these inhibitory pathways, pomalidomide facilitates an environment where immune cells can function optimally, enhancing their capacity to combat cancer cells. This intricate molecular action not only underscores pomalidomide’s unique position among treatment modalities but also sheds light on its potential as a cornerstone in myeloma therapy.

Furthermore, the clinical implications of pomalidomide’s utilization are compelling. According to the findings discussed in the editorial, patients receiving pomalidomide in conjunction with traditional therapies experienced an extended duration of progression-free survival—20.7 months against 11.6 months for those without the drug. Such stark differences in outcomes illustrate the promise that immunomodulatory agents hold in managing multiple myeloma, presenting a beacon of hope for patients undergoing this arduous journey.

Observational studies suggest that the immune-enhancing effects of pomalidomide may contribute to its superior performance in patients with relapsed or refractory myeloma. Given that the disease frequently recurs despite prior interventions, the restoration of immune functionality could serve as a strategic advantage in curtailing disease progression. Researchers advocate for a paradigm shift wherein the immunomodulatory properties of POM are deliberately leveraged to optimize treatment protocols for vulnerable patient populations.

Cancer research frequently emphasizes that the immune system’s ability to recognize and eliminate tumors is a critical determinant of therapeutic success. The comprehensive analysis presented in the editorial encapsulates a broader narrative—the evolving understanding of the interplay between immunotherapy and conventional cancer treatments. By establishing a symbiotic relationship between these approaches, clinicians may significantly enhance treatment efficacy and patient survival rates in multiple myeloma.

Pomalidomide’s potential extends beyond mere disease management; it also embodies a novel strategy aimed at re-establishing immune competence in a demographic often marginalized by suboptimal responses to traditional therapies. The urgent need for new strategies in managing multiple myeloma—a condition notorious for its resilience—accentuates pomalidomide’s role as an invaluable adjunct therapy.

As researchers continue to elucidate the precise mechanisms and optimal administration of pomalidomide, ongoing clinical trials are likely to provide further insights into its benefits and potential combinations with other agents. The editorial serves as a clarion call for continued investigation into combinatorial therapies that harness immune modulation alongside established regimens, ultimately striving for better patient outcomes and quality of life.

The integration of cutting-edge research into clinical practice is paramount for realizing the full potential of immunotherapy in treating hematological malignancies. Pomalidomide exemplifies how targeted approaches can yield substantial improvements in patient management, encouraging a deeper exploration into this category of drugs as frontline therapies.

In summation, the editorial encapsulates a critical juncture in the therapeutic landscape of multiple myeloma, where pomalidomide’s immune-boosting properties signify a transformative approach in combatting a persistently challenging disease. As the field moves forward, the hope is that a harmonization of immunotherapy with traditional treatments will not only enhance patient outcomes but also redefine the long-term management of multiple myeloma, fostering a future where remission and survivorship are possible for a greater number of patients.

Subject of Research: Cells
Article Title: Pomalidomide improved immune profiles in myeloma
News Publication Date: 14-Jan-2025
Web References: Oncoscience
References: DOI
Image Credits: © 2025 Seah et al.

The critical focus of this research lies in understanding how acute HPV infections evolve into chronic conditions, particularly since the majority of HPV infections tend to resolve spontaneously within two years. The gathered data suggests a pronounced increase in viral load shortly after infection, which is succeeded by a prolonged plateau, a phenomenon that can significantly influence treatment and preventive strategies against this prevalent infection.

In the PAPCLEAR cohort study, a total of 189 women aged between 18 and 25 years were followed for up to 24 months, where researchers adopted a methodical approach to monitor viral kinetics and immune responses every two months. This regimen allowed for unprecedented temporal resolution, providing a granulated understanding of how HPV infections operate at both the viral and immune response levels over time.

The findings suggest that non-persistent infections exhibit distinct viral load characteristics, particularly a plateau phase starting at about two months post-infection, which can last for an extended period of 13 to 20 months before a steep decline is observed. This plateau is crucial as it indicates a sustained presence of the virus in the body, raising questions about the immune responses triggered during this timeframe and their implications for long-term health outcomes.

Further analysis revealed a compelling connection between the levels of HPV viral load and specific immune cell populations, notably TCRγδ cells, which straddle the line between innate and adaptive immune responses. This correlation underscores the complexity of the immune system’s interaction with viral infections and hints at the possibility of targeted immune modulation as an avenue for clinical intervention.

Despite these groundbreaking observations, the study does face limitations, including instances where participants were already infected at the study’s inception, or instances where follow-ups were truncated. Such limitations hinder broader conclusions concerning the differences between chronic and acute infections, indicating the need for longer-term studies to substantiate these initial findings.

Notably, the authors express a pivotal perspective regarding asymptomatic HPV infections, implying that understanding their dynamic nature is essential to comprehend how these infections transition between acute and chronic states. They stress that HPV infections may correlate with unique immune response patterns localized in the genital area. The implications of these dynamics extend far beyond just individual health, highlighting the necessity for public health strategies that encompass education and vaccination efforts as intertwined components of cancer prevention tactics.

As the study illuminates the dynamics of HPV infections, it fosters hope for advancements in treatment, screening programs, and vaccination strategies aimed at alleviating the public health burden associated with HPV. The insights gleaned from this research can catalyze significant shifts in clinical approaches to HPV management, focusing on tailored interventions based on immune response characteristics and viral kinetics observed during early infection phases.

This innovative study not only propels the scientific understanding of HPV but also acts as a catalyst for future investigations into long-term health consequences for females carrying these infections. By enhancing collaborative efforts across various healthcare sectors and promoting research integrity, the scientific community can foster solutions for combating HPV-related health challenges in diverse populations.

Overall, Samuel Alizon and his colleagues have paved a promising pathway in HPV research, presenting critical data that empowers healthcare practitioners and researchers. This pursuit of knowledge aims to foster a society where the implications of HPV infections are fully understood and addressed, leading to better health outcomes and reduced incidence of HPV-related cancers.

Subject of Research: People
Article Title: Viral and immune dynamics of genital human papillomavirus infections in young women with high temporal resolution
News Publication Date: January 21, 2025
Web References: Link to the paper
References: Tessandier N, Elie B, Boué V, Selinger C, Rahmoun M, Bernat C, et al. (2025) Viral and immune dynamics of genital human papillomavirus infections in young women with high temporal resolution. PLoS Biol 23(1): e3002949.
Image Credits: Modified by Samuel Alizon from Tessandier et al., 2025, PLOS Biology, CC-BY 4.0

Keywords: HPV, viral load, immune response, cervical cancer, longitudinal study, TCRγδ cells, chronic infection, acute infection, public health, vaccination, PLOS Biology, PAPCLEAR cohort.