What Are the Biggest Unanswered Questions in Cancer Research?

In 2020, there were an estimated 18.1 million new cancer cases worldwide, with this figure expected to increase to around 28 million new cases per year by 2040. 

Understanding the biological processes that underpin cancer development and progression is key to making headway in improving prevention, early detection, screening, diagnosis, and treatment. As part of the battle against cancer, avenues of cancer research are expanding. 

At the frontier of cancer research, scientists are pioneering efforts to learn how cancer metastasizes, how to activate the immune system against cancer, how to enhance immunotherapies, and identify whether exercise can improve treatment outcomes. 

The American Association for Cancer Research (AACR) recently announced the recipients of its Trailblazer Cancer Research Grants, which award nine early-stage investigators and six mid-career investigators with $1 million each over three years.  

This funding aims to support these researchers as they establish innovative projects that will advance our understanding of cancer biology, improve patient outcomes, and drive groundbreaking translational science. 

Technology Networks spoke to some of the early-stage researchers who received the Trailblazer Grant to ask: What is the biggest unanswered scientific question at the heart of your project, and if you solve it, how could it change our understanding of cancer biology? 

Jessalyn Ubellacker, MD, PhD. Assistant professor, Harvard T.H. Chan School of Public Health 

“The biggest unanswered question at the heart of the Ubellacker Laboratory AACR Trailblazer Cancer Research Grant project is investigating the extent to which lymph nodes actively determine which cancer cells survive, die, and become visible to the immune system.  

“Lymph node involvement is a major clinical predictor of poor outcome in many cancers, yet we still know relatively little about how this unique, immune-rich microenvironment shapes metastatic cell fate.  

“My prior work during my postdoctoral training in Dr. Sean Morrison’s Laboratory at UT Southwestern in Dallas showed that melanoma cells traveling through the lymph can be protected from ferroptosis, a form of iron-dependent cell death driven by lipid peroxidation.  

“This project asks whether that protection can be redirected. Specifically, can one exploit the lipid changes that occur in lymph node metastases to make cancer cells more vulnerable, while also activating the immune system against cancer?  

“Solving this would shift how we think about lymph nodes: not just as sites where metastases are detected, but as biologically active niches that can either support metastatic survival or be reprogrammed to promote immune clearance.”

Theo Roth, MD, PhD. Assistant professor of pathology, Stanford University 

“Cancer is the leading killer of Americans, and one of the most difficult diagnoses patients face. Luckily, we are not alone in that fight—our own immune system can recognize cancers and even eliminate them, often before we become aware that we ever had a cancer. But as powerful as the immune system is, cancer has a unique ability that our immune system cannot match. Because cancers constantly mutate their DNA, they are always evolving new functions and new ways to get around the immune system. In contrast, our immune cells fight this changing threat with their hands tied behind their back. Immune cells have no way to match the adaptability of cancers to evolve and overcome the ways the immune system is trying to attack them. My research focuses on leveling the playing field—can we modify the DNA of immune cells to improve their function the same way cancer cells modify their DNA to overcome our immune system? Can we fight fire with fire? 

“There are hundreds of ways to modify immune cells to overcome cancer, and in many cases, these modified immune cell drugs have led to dramatic cures. But these cures have been inconsistent—engineered T-cell therapies work extremely well in some patients, but show little or no effect in others. A central goal of my current research is to comprehensively understand this variability, so that the right modifications are made in the right patient’s cells to treat their specific cancer. 

“The problem we face is vast—there are hundreds of immune cell modifications to examine across the incredible diversity of cancer patients. To overcome these challenges, we have developed a new technical approach called CRISPR-All, which allows every potential modification in immune cells to be tested head-to-head in dozens of cancer patients’ immune cells simultaneously. By simply asking which of the available modifications works best in each individual patient’s cells, rather than assuming that all patients will behave the same, we hypothesize that we will show that just as every patient’s cancer is unique, the ideal modified immune cell therapy for their cancer is just as unique. This could expand access to these breakthrough medicines across the diversity of patients battling cancer.” 

Justin Milner, PhD. Assistant professor, University of North Carolina at Chapel Hill 

“T cells are powerful mediators of antitumor immunity, yet their activity is frequently constrained within the solid tumor microenvironment. Advances in gene engineering, genome editing, and synthetic biology now provide unprecedented opportunities to redesign T-cell behavior to better function within tumors. 

“Early engineering approaches focused on improving trafficking, persistence, or providing sustaining signals such as IL-15. However, an increasingly important question is what biological features most fundamentally limit T-cell performance in tumors and whether these constraints can be overcome through more extensive cellular reprogramming. For example, engineering approaches may allow T cells to access functional properties or cell states not normally observed during endogenous immune responses, including enhanced stress tolerance, metabolic adaptation, tissue retention, or resistance to suppressive cues in the tumor microenvironment.  

“At the same time, as engineered T cells become increasingly potent, precise mechanisms to spatially and temporally regulate their activity will become important to minimize immune-related toxicities and off-tumor tissue damage. Defining how to maximize antitumor function while maintaining safety represents a central challenge for the next generation of cancer immunotherapy.” 

Nathan Parker, MPH, PhD. Assistant member, Department of Health Outcomes and Behavior, Moffitt Cancer Center 

“The unanswered scientific question at the heart of our project is whether an exercise ‘prehabilitation’ program with aerobic and resistance training can enhance patient-centered and clinical outcomes among hematological cancer patients undergoing CAR-T therapy. If our study demonstrates that the exercise program helps patients prepare for, tolerate, and recover from CAR T, it could represent a scalable strategy to improve CAR-T access and delivery.”