The Garcia-Beltran Lab at the Ragon Institute, led by Wilfredo Garcia-Beltran, MD, PhD, has received a National Institutes of Health (NIH) High-Risk, High-Reward Research (HRHR) Program award to propel a new project that retools natural killer (NK) cells to better locate, enter, and destroy solid tumors. The HRHR program, part of the NIH Common Fund, backs unusually bold, creative ideas with the potential for broad impact across biomedicine.

Administered by the NIH Common Fund, the HRHR portfolio (which includes the Pioneer, New Innovator, Transformative Research, and Early Independence Awards) supports unconventional approaches to big scientific challenges and spans all career stages.

Garcia-Beltran’s project addresses three obstacles that limit NK-cell treatments against solid tumors: tumor resistance to NK cells, poor NK-cell infiltration and survival inside tumors, and CAR designs (synthetic proteins engineered to make immune cells target cancer) optimized for T cells rather than NK cells. The team will use genome-wide CRISPR screens to uncover “innate immune checkpoints” in NK cells, mine single-cell tumor data to add homing and survival programs, and run high-throughput “CARpool” screens to identify next-generation, NK-tailored CARs—aiming for potent, potentially off-the-shelf therapies with a safer side-effect profile than current options.

“High-Risk, High-Reward” support is designed to accelerate this kind of cross-disciplinary, paradigm-shifting work by pairing discovery-stage immunology with synthetic biology and rigorous screening. If successful, the effort could lay the groundwork for universal CAR NK-cell products against cancers such as lung, breast, prostate, and colorectal tumors, broadening access and improving outcomes for patients.