As the most common pediatric brain malignancy, medulloblastoma (MB) includes multiple distinct molecular subtypes characterized by clinical heterogeneity and genetic alterations. Accurate identification of MB subtypes is...As the most common pediatric brain malignancy, medulloblastoma (MB) includes multiple distinct molecular subtypes characterized by clinical heterogeneity and genetic alterations. Accurate identification of MB subtypes is essential for downstream risk stratification and tailored therapeutic design. Existing MB subtyping approaches perform poorly due to limited cohorts and severe batch effects when integrating various MB data sources. To address these concerns, we propose a novel approach called RaMBat for accurate MB subtyping from diverse data sources with severe batch effects. Benchmarking tests based on 13 datasets with severe batch effects suggested that RaMBat achieved a median accuracy of 99%, significantly outperforming state-of-the-art MB subtyping approaches and conventional machine learning classifiers. RaMBat could efficiently deal with the batch effects and clearly separate subtypes of MB samples from diverse data sources. We believe RaMBat will bring direct positive impacts on downstream MB risk stratification and tailored treatment design.
Yes-associated protein (YAP) is a key oncogenic effector and a well-established driver of resistance to anticancer therapies, especially in tumors harboring KRAS mutations. Although YAP is clinically relevant, drug-devel...Yes-associated protein (YAP) is a key oncogenic effector and a well-established driver of resistance to anticancer therapies, especially in tumors harboring KRAS mutations. Although YAP is clinically relevant, drug-development efforts that directly inhibit its activity have been limited. Here, we show that basroparib-a selective tankyrase (TNKS) inhibitor that suppresses Wnt signaling-attenuates YAP-driven oncogenic programs by stabilizing angiomotin (AMOT), an endogenous negative regulator of YAP. In colorectal cancer (CRC) cells, basroparib increased AMOT protein abundance, promoted AMOT-YAP complex formation, and enforced cytoplasmic sequestration of YAP, thereby dampening YAP-dependent transcription. Basroparib preferentially sensitized YAP-overexpressing, KRAS-mutant CRC cell lines to MEK inhibition by inhibiting YAP signaling. In MEK inhibitor-resistant CRC models, in which elevated YAP activity mediates escape, basroparib restored drug sensitivity both in vitro and in vivo. The compound also enhanced MEK inhibitor efficacy in other YAP-active tumor types, while exerting minimal effects in YAP-inactive models. Taken together, these results identify basroparib-now progressing through clinical development (Phase I, NCT04505839)-as a promising agent for dual Wnt-YAP pathway blockade and for overcoming therapeutic resistance in YAP-driven cancers.
PI3K inhibitors (PI3Ki) have shown promise in some hematological cancers, but further development has been hampered by reports of serious immune-related adverse effects. Thus, identification of effective PI3Ki lacking th...PI3K inhibitors (PI3Ki) have shown promise in some hematological cancers, but further development has been hampered by reports of serious immune-related adverse effects. Thus, identification of effective PI3Ki lacking these adverse effects is desirable. Here, we evaluated the in vitro effects of the investigational PI3Ki roginolisib (IOA-244) and the approved PI3Ki idelalisib on immune cells and leukemic cells. Roginolisib inhibited chronic lymphocytic leukemia cell signaling and viability in a manner comparable to idelalisib. Both drugs specifically inhibited PI3K-signaling in T cells, validating their on-target effects. Both idelalisib and roginolisib reduced regulatory T-cell frequency in a concentration-dependent manner, with idelalisib demonstrating greater potency. Both inhibitors also reduced T-cell activation and proliferation, but to differing extents. However, only idelalisib induced a pronounced impairment of CD8 T-cell cytotoxic function. Furthermore, idelalisib treatment promoted differentiation of conventional CD4 T cells into Th1, Th2, and Th17 subsets-a response not observed with roginolisib. In summary, roginolisib functions as an effective PI3K inhibitor on leukemic cells while preserving T-cell functions, posing it as an alternative to current PI3K inhibitors.
Triggering receptor expressed on myeloid cells 2 (TREM2) has emerged as a key immunosuppressive target on tumour-associated macrophages (TAMs), where it coordinates protumorigenic and anti-inflammatory functions within t...Triggering receptor expressed on myeloid cells 2 (TREM2) has emerged as a key immunosuppressive target on tumour-associated macrophages (TAMs), where it coordinates protumorigenic and anti-inflammatory functions within the tumour microenvironment (TME). Unfortunately, recent clinical evidence indicates that therapeutic TREM2 blockade has suboptimal efficacy in cancer patients. Now, Von Locquenghien et al. report that MiTE-144, a TREM2 blocking antibody fused to an IL2 variant with TME-restricted activation, demonstrates superior anticancer efficiency compared to TREM2 blockade alone in the preclinical setting. Importantly, MiTE-144 showed reduced systemic inflammation or hepatotoxicity relative to TREM2 blockade and/or 'generic' IL2 immunocytokine approaches. Detailed TME analysis of MiTE-144-treated tumours showed substantial reprogramming of the myeloid compartments, together with activation of NK/CD8 T cells. While this study tackled several limitations of anti-TREM2 monotherapy, more attention is needed towards clinically relevant immunotherapy barriers in therapy-refractory tumour settings.
PIK3R1, a regulatory subunit of class IA phosphoinositide-3-kinase (PI3K), undergoes alternative splicing to generate multiple isoforms, primarily p85α and p55α. The canonical isoform p85α associates with the catalytic s...PIK3R1, a regulatory subunit of class IA phosphoinositide-3-kinase (PI3K), undergoes alternative splicing to generate multiple isoforms, primarily p85α and p55α. The canonical isoform p85α associates with the catalytic subunit p110α to form the active PI3K complex, which regulates key cellular functions such as growth, proliferation, survival, and metabolism. In this study, we performed a comprehensive pan-cancer analysis integrating transcriptomic, proteomic, and genomic data to investigate the expression patterns of p85α and its splicing variant, p55α, and their associations with clinical outcomes. Our findings reveal that while p85α expression is significantly reduced, p55α is elevated in tumors as compared to normal samples. These alterations are linked to poor prognosis across multiple cancer types. Notably, we observed racial disparities in expression patterns, with African American patients exhibiting more pronounced downregulation of p85α and upregulation of p55α than European Americans, potentially contributing to differential clinical outcomes. This is the first study to systematically evaluate p85α and p55α expression across diverse cancers and populations, highlighting the role of alternative splicing in PI3K pathway dysregulation and its relevance to cancer progression and health disparities.
Traditionally, cancer has been viewed largely as a disease of the cell, with extensive research centred on how mutations in driver genes trigger cellular transformation. Beyond cell-intrinsic changes, cancer unfolds as a...Traditionally, cancer has been viewed largely as a disease of the cell, with extensive research centred on how mutations in driver genes trigger cellular transformation. Beyond cell-intrinsic changes, cancer unfolds as a systemic disease driven by an intricate dialogue between malignant cells and the host's organs and tissues. Modelling this multilayered phenomenon is challenging, as it requires recapitulating coordinated interactions within and across multiple organs, inside an organism that is contended with maintaining normal physiology. In recent years, Drosophila melanogaster has emerged as a powerful model for revealing fundamental mechanisms by which the tumour and host mutually interact. In this review, we highlight recent findings that unravel the intricacies of tumour-host biology using Drosophila. At the microenvironment level, we synthesise mechanistic findings on how tumour growth is modulated through interactions with neighbouring tumour subclones, nonmutated wild-type cells and the immune system. At the macroenvironment level, work in Drosophila has provided mechanistic insights into how tumourigenesis causes systemic host health degeneration and accelerates death, collectively termed paraneoplastic effects. Tumours can remotely induce systemic metabolic rewiring and cachectic tissue wasting to promote progression, while simultaneously compromising the function of several tissues, such as the renal system, blood-brain barrier, the gut and blood haemostasis. Additionally, we discuss how the microbiota and sexual dimorphism have been shown to affect the tumour-host interplay. With this review, we synthesise recent advances in Drosophila tumour-host biology and illustrate how this model illuminates cancer's systemic nature.
Ritchie D, Crowley Q, Greinert R
… +15 more, Albin M, Baldi I, Consonni D, Fervers B, Hoek G, Jochems SHJ, Röösli M, van Tongeren M, Vilahur N, Feliu A, Zeeb H, Schüz J, D'Souza E, Espina C, Kromhout H
The European Code Against Cancer (ECAC) provides evidence-based recommendations to help individuals reduce their cancer risk. For the 5th edition (ECAC5), recommendations on ultraviolet radiation (UVR) and indoor radon e...The European Code Against Cancer (ECAC) provides evidence-based recommendations to help individuals reduce their cancer risk. For the 5th edition (ECAC5), recommendations on ultraviolet radiation (UVR) and indoor radon exposures were updated, and complementary recommendations for policymakers were introduced. UVR and radon are classified as carcinogenic to humans (group 1 carcinogens) in the International Agency for Research on Cancer (IARC) Monographs. Solar UVR and, to a lesser extent, artificial forms of UVR exposure are major causes of skin cancer, while radon gas is a leading cause of lung cancer. This paper summarises the evidence for retaining and refining these recommendations. For individuals, ECAC5 advises avoiding excessive sun exposure, especially in children, using sun protection, and never using sunbeds; for radon, checking local radon maps, seeking professional measurement where appropriate and taking remedial action, if necessary, are recommended. For policymakers, ECAC5 encourages harmonised UVR protection measures across the European Union, enforcement of regulations concerning indoor tanning devices, and enabling access to testing of radon levels, and support for mitigation and remediation. These recommendations provide actionable, evidence-based recommendations to help reduce cancer risk and align with Europe's Beating Cancer Plan.
Alberts CJ, Bloem P, de Sanjosé S
… +16 more, Grabar S, Leja M, Malfertheiner P, Matičič M, Mégraud F, Negro F, Plummer M, Schim van der Loeff M, Balbín G, Salazar J, Zeeb H, Feliu A, D'Souza E, Ritchie D, Espina C, Franceschi S
The main infections that cause cancer in the European Union (EU) are Helicobacter pylori (H. pylori), human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). A...The main infections that cause cancer in the European Union (EU) are Helicobacter pylori (H. pylori), human papillomavirus (HPV), hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV). Altogether, in 2022, these infections accounted for ~ 5% of all cancers in the EU, mainly of the stomach, cervix uteri and liver. The largest burden of infection-caused cancers was found in the south of the EU and near the eastern border. Substantial progress in the efficacy of interventions against these infections has been made since the release of the 4th edition of the European Code Against Cancer in 2015. Cancers due to infections can increasingly be prevented by prophylactic vaccines (HPV and HBV) and/or prompt diagnosis and treatment that can either cure (HCV and H. pylori) or slow down the infection (HBV and HIV), thus substantially reducing disease risk. Tools to tackle carcinogenic infections are also increasingly accessible and affordable in the EU, but their implementation is slow. Public awareness, political will and cost-effective protocols are necessary to establish large programmes of vaccination or testing and treatment. Progress monitoring, as well as avoiding disinformation and stigma, is crucial to ensure that advances in medical progress are fully leveraged. The recently published 5th edition of the European Code Against Cancer therefore recommends: (1) vaccinate girls and boys against HBV and HPV at the age recommended in your country; (2) take part in testing and treatment for HBV and HCV, HIV and H. pylori, as recommended in your country.
Although cancer is a leading cause of death in the European Union, around 40% of cases are preventable. The European Code Against Cancer (ECAC) was developed to inform citizens about key cancer-risk-reducing actions. Thi...Although cancer is a leading cause of death in the European Union, around 40% of cases are preventable. The European Code Against Cancer (ECAC) was developed to inform citizens about key cancer-risk-reducing actions. This study aimed to identify effective ways to present the 5th edition of the code (ECAC5) to optimise awareness of cancer risks in all socioeconomic groups. Using a 2 × 3 × 2 factorial design, 10 027 participants from eight countries were randomised online to receive 'no message' or one of 10 ECAC5 formats differing in message content (cancer risks: present/absent), length of message on cancer prevention actions (longer/shorter/absent) or format (text-only/text with images). The primary outcome was awareness of 16 avoidable cancer risks. Overall mean number of risks recalled was 2.40 (standard deviation: 1.72; range 0-14). Recall was highest when messages included risk information. Adding prevention messages to risk information did not improve risk factor recall. Message length and images had no significant impact. Effects were similar across levels of education and countries. Combined information about risk factors and preventive actions has the potential to equitably increase citizens' very low cancer prevention awareness. How this awareness might change over time or lead to behaviour change is unknown and should be the focus of future evaluations.
Hoek G, van Tongeren M, Röösli M
… +15 more, Jochems SHJ, Vilahur N, Albin M, Baldi I, Crowley Q, Fervers B, Greinert R, Consonni D, Feliu A, Zeeb H, Schüz J, D'Souza E, Ritchie D, Espina C, Kromhout H
Most European Union (EU) residents live in areas where outdoor air pollution levels exceed the 2021 World Health Organization (WHO) air quality guidelines for fine particles and nitrogen dioxide. Outdoor air pollution is...Most European Union (EU) residents live in areas where outdoor air pollution levels exceed the 2021 World Health Organization (WHO) air quality guidelines for fine particles and nitrogen dioxide. Outdoor air pollution is classified as carcinogenic to humans, and both outdoor and indoor air contain established human carcinogens, including diesel exhaust particulates, benzo(a)pyrene [B(A)P] and benzene. The European Code Against Cancer, 5th edition (ECAC5), incorporates recommendations for individuals and policymakers aimed at reducing the cancer burden from both outdoor and indoor air pollution. A critical step is aligning EU air quality limit values with the more stringent 2021 WHO guidelines. This should be complemented by integrated policy measures, including stricter regulation of combustion emissions, promotion of active and environmentally friendly transportation, incentives for cleaner energy sources for heating and cooking, and harmonization with broader EU climate initiatives. At the individual level, emissions and exposure may be reduced by limiting car use, avoiding second-hand smoke, and refraining from burning wood or coal indoors or outdoors. Further exposure reduction may be achieved by limiting walking or cycling along heavily trafficked routes.
Leitzmann MF, Bakogianni I, Anderson AS
… +17 more, Bauld L, Fernandez E, Morris S, Srour B, Vardavas C, Vlad I, Vuik S, Weijenberg M, Figuls MRI, Rigau D, Feliu A, Zeeb H, Schüz J, D'Souza E, Ritchie D, Espina C, Riboli E
Diet, body weight, physical activity, sedentary behavior, and breastfeeding are modifiable factors influencing the cancer burden in the European Union, shaped by underlying social, commercial, environmental, and behavior...Diet, body weight, physical activity, sedentary behavior, and breastfeeding are modifiable factors influencing the cancer burden in the European Union, shaped by underlying social, commercial, environmental, and behavioral conditions. Excess body weight has reached epidemic levels, significantly influenced by widespread intake of sugar-sweetened beverages and ultra-processed foods rich in sugar, fat, and salt. Consumption of red and processed meat also commonly exceeds dietary recommendations. Physical inactivity and prolonged sedentary behavior are widespread. Breastfeeding rates vary widely across Europe but are generally low, particularly in high-income countries. To reduce cancer risk, the European Code Against Cancer, 5th edition (ECAC5) recommends a diet rich in whole grains, vegetables, legumes, and fruits, while limiting red meat and avoiding processed meat. Intake of vegetables, legumes, and fruits prevents aerodigestive tract cancers, while diets high in whole grains and low in red and processed meat reduce colorectal cancer risk. Avoiding excess body weight through diet and physical activity, and limiting prolonged sitting, decreases risk of numerous cancers. Promoting and supporting sustained breastfeeding contributes to lowering breast cancer risk. Key policy interventions, such as fiscal incentives, urban planning, marketing restrictions, and public awareness campaigns, are central to creating supportive environments for cancer prevention.
The European Code Against Cancer (ECAC) provides evidence-based public health recommendations to reduce cancer risk across Europe. First launched in 1987, it is periodically updated mainly to reflect scientific advances....The European Code Against Cancer (ECAC) provides evidence-based public health recommendations to reduce cancer risk across Europe. First launched in 1987, it is periodically updated mainly to reflect scientific advances. The 5th edition (ECAC5), released for the medical oncology community in 2025 and to be presented to the public in 2026, aims to offer an authoritative and practical tool for cancer prevention for individuals and policymakers. Developed by over 60 experts across five Working Groups, ECAC5 expands the 12 recommendations of the 4th edition to 14, incorporating the latest evidence on modifiable cancer risks and effective medical interventions. Key innovations include new guidance on air pollution, cancer-related infections, lung cancer screening and strengthened recommendations on tobacco, alcohol, diet, body weight, and occupational and radiation exposures. A major advancement is the addition of dedicated policy recommendations, acknowledging that many prevention measures require supportive environments and regulation. By aligning cancer prevention with broader noncommunicable disease strategies, ECAC5 aims to enhance uptake and impact. Its effective implementation could prevent up to 40% of new cancers in the EU.
Knowledge mobilisation is essential in cancer prevention to equip individuals with the knowledge to reduce their risk and improve their health. Hence, dissemination of evidence-based recommendations is a key tenet in the...Knowledge mobilisation is essential in cancer prevention to equip individuals with the knowledge to reduce their risk and improve their health. Hence, dissemination of evidence-based recommendations is a key tenet in the fight to reduce the burden of cancer in the European Union (EU). Systems thinking was used to guide the methods of three substudies involving stakeholders in identifying dissemination actions to enhance the awareness and uptake of the European Code Against Cancer, 5th edition (ECAC5), including mapping barriers and facilitators to achieve impactful dissemination. The proposed actions aimed to foster collaboration and partnership across diverse sectors, utilising diverse and accessible channels to deliver visually engaging content to maximise the delivery and impact of the ECAC5 to the general public in the EU. Many of these actions were evaluated by participants as highly feasible and impactful, thereby supporting their implementation.
Jochems SHJ, Vilahur N, van Tongeren M
… +15 more, Albin M, Baldi I, Consonni D, Crowley Q, Fervers B, Greinert R, Hoek G, Röösli M, Zeeb H, Schüz J, Feliu A, D'Souza E, Ritchie D, Espina C, Kromhout H
Occupational exposure to cancer-causing agents is a major, yet preventable, contributor to cancer in Europe and globally. In the European Union (EU), cancer is responsible for nearly half of all work-related deaths, unde...Occupational exposure to cancer-causing agents is a major, yet preventable, contributor to cancer in Europe and globally. In the European Union (EU), cancer is responsible for nearly half of all work-related deaths, underscoring the critical need for prevention measures. Effective strategies typically involve regulatory and workplace measures aimed at reducing or eliminating exposure risks. Raising awareness of hazardous workplace exposures is essential to empower individuals, foster a culture of prevention, and support effective regulation. The 5th edition of the European Code Against Cancer (ECAC5) includes a recommendation on how individuals can minimize their cancer risk and highlights the shared responsibilities of workers and employers for occupational safety and health: 'Inform yourself about cancer-causing factors at work and call on your employer to protect you against them. Always follow health and safety instructions at your workplace'. Key to ECAC5 is the addition of policy pointers at the governance level to support employers in taking preventive action and improving worker awareness. Strengthening regulatory frameworks and increasing awareness are crucial steps toward reducing the burden of occupational cancer.
Toes-Zoutendijk E, Arbyn M, Auvinen A
… +17 more, Baldwin D, Castells X, DeCensi A, Hofvind S, Ivanus U, Senore C, Thorat M, van der Aalst C, Pinto ACPN, Bracchiglione J, Feliu A, Zeeb H, D'Souza E, Ritchie D, Espina C, Carvalho AL, Lansdorp-Vogelaar I
The 5th edition of the European Code Against Cancer (ECAC5) recommends sustainable, organised screening programmes for: (a) colorectal cancer using biennial quantitative faecal immunochemical test (FIT) for individuals a...The 5th edition of the European Code Against Cancer (ECAC5) recommends sustainable, organised screening programmes for: (a) colorectal cancer using biennial quantitative faecal immunochemical test (FIT) for individuals aged 50-74 years. As an alternative strategy, once-only endoscopy may be considered within the same age range; (b) breast cancer using biennial digital mammography for women aged 50-69 years. Implementing this strategy for women aged 45-49 years and 70-74 years can be considered. Other screening strategies or additional examinations could be considered for women with high mammographic density; (c) cervical cancer using human papillomavirus (HPV) screening at intervals no shorter than 5 years for women aged 30-65 years. It is recommended to adapt policies according to vaccination status and screening history; and (d) lung cancer using annual low-dose computed tomography (LDCT) for individuals considered to be at increased risk of lung cancer based on age, history of smoking or validated risk models, with biennial screening as an alternative. Screening should incorporate smoking cessation interventions.
Feliu A, Anderson AS, Bauld L
… +17 more, Fernández E, Leitzmann M, Morris S, Srour B, Vardavas C, Vlad I, Vuik S, Weijenberg M, Alvarado-Villacorta R, Canelo-Aybar C, Zeeb H, Schüz J, D'Souza E, Ritchie D, Espina C, Bakogianni I, Riboli E
Tobacco use, second-hand tobacco smoke (SHS) exposure and alcohol consumption are well-established carcinogens and major public health concerns. In the European Union (EU), tobacco and alcohol use are the leading prevent...Tobacco use, second-hand tobacco smoke (SHS) exposure and alcohol consumption are well-established carcinogens and major public health concerns. In the European Union (EU), tobacco and alcohol use are the leading preventable causes of cancer and four other major noncommunicable diseases (NCDs), significantly contributing to NCD-related morbidity and mortality. Despite declining prevalence, consumption of these substances is still high in the region, especially among the most deprived. There is strong evidence that quitting smoking, minimising exposure to SHS and eliminating or reducing alcohol intake substantially lowers the risk of cancer. Comprehensive public health strategies at both the individual and population level are crucial to prevent cancer and other NCDs. Scientific evidence leads to two recommendations for individual action on tobacco in the European Code Against Cancer, 5th edition: (1) 'Do not smoke. Do not use any form of tobacco, or vaping products. If you smoke, you should quit'; and (2) 'Keep your home and car free of tobacco smoke'; and one on alcohol: (3) 'Avoid alcoholic drinks'.
Gordon N, Gallagher PT, Richter OI
… +11 more, Poudel Neupane N, Mandigo AC, McCann JJ, Dylgjeri E, Vasilevskaya I, McNair C, Paller CJ, Kelly WK, Knudsen KE, Schiewer MJ, Shafi AA
Prostate cancer (PCa) is the second leading cause of cancer-related death among men in the United States. While organ-confined disease has a reasonable expectation of cure, metastatic PCa is universally fatal upon recurr...Prostate cancer (PCa) is the second leading cause of cancer-related death among men in the United States. While organ-confined disease has a reasonable expectation of cure, metastatic PCa is universally fatal upon recurrence during hormone therapy, a stage termed castration-resistant prostate cancer (CRPC). Until such time as molecularly defined subtypes can be identified and targeted using precision medicine, it is necessary to investigate new therapies that may apply to the entire CRPC population. The use of ascorbate, more commonly known as ascorbic acid or Vitamin C, has demonstrated antitumor activity in a variety of cancer cell types. There are several mechanisms currently under investigation to explain how ascorbate exerts anticancer effects. A simplified model depicts ascorbate as a pro-drug for reactive oxygen species (ROS), which accumulate intracellularly and generate DNA damage. It was therefore hypothesized that poly (ADP-ribose) polymerase (PARP) inhibitors, by inhibiting DNA damage repair, would augment the toxicity of ascorbate, leading to improved antitumor effects. Two distinct CRPC models were found to be sensitive to physiologically relevant doses of ascorbate. Moreover, additional studies indicate that ascorbate inhibits CRPC growth in vitro via multiple mechanisms including disruption of cellular energy dynamics and accumulation of DNA damage. Combination studies were performed in CRPC models with ascorbate in conjunction with escalating doses of three different PARP inhibitors (niraparib, olaparib, and talazoparib). The addition of ascorbate augmented the toxicity of all three PARP inhibitors and proved synergistic effects with olaparib in both CRPC models. Finally, the combination of olaparib and ascorbate was tested in vivo in both castrated and noncastrated models. In both cohorts, the combination treatment significantly delayed tumor growth compared to monotherapy or untreated control. These data indicate that pharmacological ascorbate is an effective monotherapy at physiological concentrations and kills CRPC cells. Ascorbate-induced tumor cell death was associated with disruption of cellular energy dynamics and accumulation of DNA damage. The addition of PARP inhibition increased the extent of DNA damage and proved effective at slowing CRPC growth both in vitro and in vivo. These findings implicate ascorbate and PARPi as a novel therapeutic regimen that has the potential to improve CRPC patient outcomes.
The protein kinase p38α is an important regulator of cell homeostasis that has been implicated in the response to many types of stresses. Given the plethora of functions that can be potentially regulated by p38α, this pa...The protein kinase p38α is an important regulator of cell homeostasis that has been implicated in the response to many types of stresses. Given the plethora of functions that can be potentially regulated by p38α, this pathway has been linked to many diseases including cancer, suggesting a potential therapeutic interest in targeting p38α. This Viewpoint focuses on the role of p38α stress signaling in cancer development and therapy, discussing recent reports and reflecting on future challenges.
PD-L1 is a key immune checkpoint ligand that suppresses antitumor immunity by engaging PD-1 on T cells. While therapeutic blockade of PD-L1/PD-1 interactions has shown clinical benefit, many patients fail to respond, ind...PD-L1 is a key immune checkpoint ligand that suppresses antitumor immunity by engaging PD-1 on T cells. While therapeutic blockade of PD-L1/PD-1 interactions has shown clinical benefit, many patients fail to respond, indicating modulation by other factors. Here, we identified a novel regulatory axis in which the membrane-organizing protein tetraspanin-4 (TSPAN4) modulates PD-L1 in melanoma cells. Using cell surface proximity biotinylation coupled with mass spectrometry, we discovered that TSPAN4 physically associates with PD-L1, with both proteins colocalizing on migrasomes and retraction fibers. Mechanistically, we show that TSPAN4 negatively regulates PD-L1 protein levels by enhancing its degradation and restricting its lateral mobility at the plasma membrane. Loss of TSPAN4 stabilized PD-L1, promoted its interaction with CMTM6, and increased PD-L1 surface availability for PD-1 binding. Functionally, TSPAN4 knockdown in melanoma cells led to more efficient immune checkpoint blockade through PD-1 on T cells. This study identifies TSPAN4 as a negative regulator of PD-L1 at the cell surface of melanoma cells suggesting that targeting TSPAN4 may offer a new therapeutic strategy to enhance immune checkpoint blockade in melanoma and other cancers.
Antibody-drug conjugates (ADCs) are rapidly expanding in the clinical treatment of cancers, and combinations with checkpoint inhibitors further enhance antitumor activity in patients sensitive to such immunotherapy. Howe...Antibody-drug conjugates (ADCs) are rapidly expanding in the clinical treatment of cancers, and combinations with checkpoint inhibitors further enhance antitumor activity in patients sensitive to such immunotherapy. However, a method to improve treatment durability, including cases where immunologically cold tumors limit checkpoint inhibitor activity, is needed. Here, we demonstrate that mixtures of ADCs and immune-stimulating antibody conjugates (ISACs) enhance efficacy compared to either agent alone. Our approach utilizes two non-competitive antibodies to increase the internalization of a tumor-associated antigen (carcinoembryonic antigen, CEA), facilitating the entry of the toxic payload (SN-38, a topoisomerase I inhibitor) into cancer cells. With improved FcγR engagement, the designed ISAC better delivered the immunostimulatory agent (STING agonist) into immune cells. After treatment, the average tumor volume in the combination group was ~40% of the ADC group, and ~30% of the PBS group at day 14. The side effects of combination therapy were tolerable, with an average weight loss of 7% or less after injections. We expect this approach can be readily extended to other ADCs to enhance their efficacy, including for the treatment of immunologically cold tumors.