Fig. 1. Schematic diagram of the interaction between indirect modifiers of the tumor microenvironment and direct tumor modifiers.

Direct tumor modifiers act on tumor cells to promote cellular death. These strategies include chemotherapy, radiation therapy, targeted therapies, and epigenetic agents. Indirect modifiers operate predominantly to shift the microenvironment to favor anti-tumor immunity. This can be achieved by enhancing the efficacy or quantity of effector T cells and APCs and/or inhibiting tolerogenic cells such as Tregs and MDSCs. Indirect modulators may also alter the microenvironment through modification of the gut microbiome, the local vasculature, the cytokine milieu, or by altering cellular metabolism, including of amino acids, glucose, and lipids. As depicted, these mechanisms do not operate in isolation, as modification of the microenvironment may enhance direct tumor cell killing and vice versa.