Embodiments of the disclosure encompass improvements on
cell therapies by allowing the cells to be more effective for
cancer treatment, including in a
solid tumor microenvironment. In specific cases, the cells are modified to have reduced or inhibited levels of expression of GPR4, GPR31, GPR68, GPR81, GPR132, GPR151, CREM, ICER, or
CREB1, such as by
CRISPR gene editing. In certain cases, the cells are modified to have reduced or inhibited levels of expression of CREM. In certain cases, the cells are further modified to express, for example, one or more engineered receptors, one or more cytokines, and / or optionally one or more suicide genes.