Targeting metabolic pathways to counter cancer immunotherapy resistance.

Immunotherapies have revolutionized the treatment of certain cancers, but challenges remain in overcoming immunotherapy resistance. Research shows that metabolic modulation of the tumor microenvironment can enhance antitumor immunity. Here, we discuss recent preclinical and clinical evidence for the efficacy of combining metabolic modifiers with immunotherapies. While this combination holds great promise, a few key areas must be addressed, which include identifying the effects of metabolic modifiers on immune cell metabolism, the putative biomarkers of therapeutic efficacy, the efficacy of modifiers on tumors harboring metabolic heterogeneity, and the potential development of resistance due to tumor reliance on alternative metabolic pathways. We propose solutions to these problems and posit that assessing these parameters is crucial for considering the potential of metabolic modifiers in sensitizing tumors to immunotherapies.

Immunomodulatory drugs: a promising clinical ally for cancer immunotherapy.

While immunomodulatory imide drugs (IMiDs) have been authorised for treatment of haematological cancers for over two decades, the appreciation of their ability to stimulate antitumour T cell and natural killer (NK) cell responses is relatively recent. Clinical trial data increasingly show that targeted immunotherapies, such as antibodies, T cells, and vaccines, improve outcomes when delivered in combination with the IMiD derivatives lenalidomide or pomalidomide. Here, we review these clinical data to highlight the relevance of IMiDs in combinatorial immunotherapy for both haematological and solid tumours. Further research into the molecular mechanisms of IMiDs and an increased understanding of their immunomodulatory effects may refine the specific applications of IMiDs and improve the design of future clinical trials, moving IMiDs to the forefront of combinatorial cancer immunotherapy.