# Cell cycle arrest enhances CD8+ T cell effector function by potentiating glucose metabolism and IL-2 signaling

## TL;DR

Stopping CD8+ T cells from dividing boosts their energy and ability to fight cancer, improving immunotherapy outcomes.

## Contribution

Transient cell cycle arrest reprograms CD8+ T cells to enhance their metabolic state and antitumor function.

## Key findings

- Cell cycle-arrested CD8+ T cells undergo metabolic reprogramming into a highly energized state.
- Enhanced glycolysis and IL-2 signaling support rapid proliferation and tumor control after release from arrest.
- Transient arrest improves CD8+ T cell efficacy in immunotherapy models like checkpoint blockade and adoptive transfer.

## Abstract

Cell cycle-inhibiting chemotherapeutics are widely used in cancer treatment. Although the primary aim is to block tumor cell proliferation, their clinical efficacy also involves specific effector CD8+ T cells that undergo synchronized proliferation and differentiation. How CD8+ T cells are programmed when these processes are uncoupled, as occurs during cell cycle inhibition, is unclear. Here, we show that activated CD8+ T cells arrested in their cell cycle can still undergo effector differentiation. Cell cycle-arrested CD8+ T cells become metabolically reprogrammed into a highly energized state, enabling rapid and enhanced proliferation upon release from arrest. This metabolic imprinting is driven by increased nutrient uptake, storage and processing, leading to enhanced glycolysis in cell cycle-arrested cells. The nutrient sensible mTORC1 pathway, however, was not crucial. Instead, elevated interleukin-2 production during arrest activates STAT5 signaling, which supports expansion of the energized CD8+ T cells following arrest. Transient arrest in vivo enables superior CD8+ T cell-mediated tumor control across models of immune checkpoint blockade, adoptive cell transfer and therapeutic vaccination. Thus, transient uncoupling of CD8+ T cell differentiation from cell cycle progression programs a favorable metabolic state that supports the efficacy of effector T cell-mediated immunotherapies.

Here the authors show that transient cell cycle arrest reprograms CD8+ T cells into a highly energized state, increasing proliferation and antitumor activity and boosting efficacy of immunotherapies in cancer models.