This article, authored by a team of researchers from various institutions, aims to understand the proximal causes of mortality in patients with cancer and propose new avenues for research and treatment. The authors highlight that while metastasis is often cited as the primary cause of cancer-related deaths, the actual mechanisms are more complex and involve multiple interconnected systems within the body. They discuss the impact of acute events such as vascular/coagulation/cardiac failure, displacement or obstruction of vital organs, infections, paraneoplastic syndromes, and therapy-induced toxicity. The article also explores the broader effects on the immune and hematopoietic systems, the nervous system, metabolism, and whole-body dysfunction. The authors recommend improved records and reporting, more detailed observational clinical studies, increasing the relevance of model systems, and clinical trials to better understand and address cancer mortality. They emphasize the importance of these efforts in developing strategies to improve the quality and duration of life for patients with advanced cancer.This article, authored by a team of researchers from various institutions, aims to understand the proximal causes of mortality in patients with cancer and propose new avenues for research and treatment. The authors highlight that while metastasis is often cited as the primary cause of cancer-related deaths, the actual mechanisms are more complex and involve multiple interconnected systems within the body. They discuss the impact of acute events such as vascular/coagulation/cardiac failure, displacement or obstruction of vital organs, infections, paraneoplastic syndromes, and therapy-induced toxicity. The article also explores the broader effects on the immune and hematopoietic systems, the nervous system, metabolism, and whole-body dysfunction. The authors recommend improved records and reporting, more detailed observational clinical studies, increasing the relevance of model systems, and clinical trials to better understand and address cancer mortality. They emphasize the importance of these efforts in developing strategies to improve the quality and duration of life for patients with advanced cancer.