Cancer Research Roundup: SPARK AI, Liver Cancer Hallmarks, and Lung Cancer in Never-Smokers
New studies present SPARK, an AI framework for tumor analysis, a Cell review of liver cancer hallmarks and treatments, and a call for more research into lung cancer in never-smokers, which was the fifth most common cause of cancer death in 2020.
Researchers have introduced SPARK, an agentic AI framework for cancer pathology, published a comprehensive review of liver cancer biology and treatments, and called for dedicated research into lung cancer in never-smokers. The findings, appearing in Nature, Cell, and Trends in Cancer, cover AI-driven tumor analysis, liver cancer hallmarks and therapeutic advances, and the distinct biology of lung cancer in people who have never smoked.
SPARK (System of Pathology Agents for Research and Knowledge) is a foundational agentic artificial intelligence approach that uses language as a universal interface to autonomously generate biologically driven concepts for tumor analysis. It works directly with complex pathology data without extra model training. SPARK was evaluated across 18 patient cohorts spanning five cancer types — lung adenocarcinoma, lung squamous cell carcinoma, colorectal cancer, breast cancer, and oropharyngeal squamous cell carcinoma — comprising more than 5,400 patients with histopathology images and clinical/follow-up information, plus a spatial biology breast cancer dataset of 625 patients. The framework produced clinically and biologically relevant concepts correlated with prognosis, known pathological variables, and predictive biomarkers, including patterns of tumor progression and temporal change inferred from static images. A dedicated module allows human interaction with SPARK. Further prospective validation is needed to evaluate the clinical utility of the tools created by SPARK. All code, parameters, and results are openly released.
A review in Cell, part of a special issue marking the 25th anniversary of the "Hallmarks of Cancer" framework, analyzes the biological characteristics of liver cancer and their therapeutic implications. Hepatocellular carcinoma (HCC) accounts for approximately 85% of liver cancer cases, while intrahepatic cholangiocarcinoma (iCCA) represents around 10%, and these tumors are often diagnosed at advanced stages. In HCC, key processes include uncontrolled cell proliferation driven by genetic alterations and the inflammatory microenvironment, angiogenesis, and the ability to evade immune surveillance. These insights have facilitated the development of anti-angiogenic agents, inhibitors of molecular pathways, and immunotherapy combinations, which have become first-line treatment in advanced disease and improved patient survival. In iCCA, metabolic alterations and specific genetic changes such as FGFR2 fusions or mutations in IDH1, ERBB2, and BRAF enable personalized treatment; approximately 45% of iCCA cases harbor alterations that can be targeted with approved or investigational therapies. The combination of chemotherapy and immunotherapy has become the standard treatment for advanced disease.
Another review, in Trends in Cancer, calls for increased funding for the screening and study of lung cancer in never-smokers (LCINS), which was the fifth most common cause of cancer death worldwide in 2020. Evidence from studies of several thousand lung cancer patients in the US and UK suggests absolute numbers of lung cancer in never-smokers have risen, with UK cases doubling between 2008 and 2014. The overwhelming majority of lung cancer screening resources are directed towards smokers, and in the UK there is no routine screening for people who have never smoked. As a result, LCINS is often diagnosed later, leading to poorer outcomes, and immunotherapy is significantly less effective in never-smokers. The review argues that LCINS has distinct causes and biology, including genetics, clonal hematopoiesis, and environmental exposures such as air pollution, radon, and second-hand smoke. Never-smokers are more likely to develop adenocarcinoma, and around 80% of lung adenocarcinomas have actionable mutations, but respond less effectively to immunotherapy compared to smokers. Up to 4.5% of people with lung adenocarcinoma carry inherited genetic variants that increase cancer risk. Potential prevention strategies include targeted prevention for those with an inherited predisposition, anti-inflammatory strategies for those with inflammation due to pollution exposure, clonal hematopoiesis of indeterminate potential, or inflammatory diseases, and public health interventions such as radon monitoring and reducing exposure to air pollution and second-hand smoke.