The realization that cellular metabolism dictates immune cell development, differentiation and function afford metabolic intervention as a potential venue for cancer immunotherapy. mTOR signaling, as a metabolic master regulator, controls immune cell biology in a cell type-specific and context-dependent manner. 

Furthermore, mTOR activity needs to be fine-tuned to maintain proper immune function. These properties may be exploited for therapeutic purpose, yet caution should be taken against radical changes of mTOR activity. Here, the intricate and complex mTOR regulation in different immune cells is reviewed, highlighting the latest discoveries and opportunities for cancer immunotherapy.

There are growing efforts to target immune cells for cancer therapy, following the success of immune checkpoint inhibitors. Researches from the burgeoning immunometabolism field point to metabolic intervention as an attractive option to improve immune responses against cancer and other immune-related diseases.

Cellular metabolism

The mTOR signaling, a master regulator of cellular metabolism, emerges as a potential target for cancer immunotherapy. However, as described above, the researchers are needed to be very cautious when we manipulate mTOR activity, or mTOR-mediated metabolism, to enhance the anti-tumor immune response.

Extensive basic research over the past few years has demonstrated that mTOR regulates immune cell homeostasis and function in a context and cell type-specific manner.

Consequently, the mTOR intervention strategy needs to be tailored for different cell types. For example, while mTOR inhibition could be adopted on DCs to generate cellular adjuvant, it is more logical to boost mTOR activity in NK cells by high-dose IL-15 for adoptive cell transfer therapy.

Furthermore, the existence of “Goldilocks mTOR”, especially in the case of CD8+ T cells and Tregs, means that mTOR activity has to be fine-tuned for proper immune functions. This is particularly true for CD8+ T cells, the most potent anti-tumor immune cells.

There is ample evidence that modulating the mTORC1 activity or mTORC1-dependent anabolic metabolism, promotes memory CD8+ T cell generation, which should benefit long-term tumor regression.

At the same time, mTORC1 activity is required for efficient effector function and recall response. Thus, it is imperative to find the right mTORC1 activity level conducive for memory formation without compromising effect T cells activity, before it is applied clinically.

In contrast, targeting mTOR in Tregs is likely to be beneficial for cancer therapy, because Treg suppressive activity can be impaired by either inhibition of mTORC1 or over-activation of mTOR activity.

While direct targeting mTOR in immune cells has been tested in a number of murine xenografts tumor models, it has yet to be tested in any spontaneous tumor models, or clinical trials.