Integrating T cell signaling and metabolism to enhance T cell engager responses in solid tumors

T cell engagers (TCEs) have delivered meaningful clinical benefit to patients, with eight molecules currently FDA-approved for hematologic malignancies and two approved for solid tumor indications. Despite their transformative potential, successful TCE development across solid tumor indications remains challenging, and additional strategies are needed to maintain T cell fitness and function within the tumor microenvironment (TME). Next-generation TCE designs aim to increase response rate and bolster durability by optimizing or delivering additional signals to T cells. In recent years, cellular metabolism has emerged as a potent regulator of T cell function and fate, shaping immunity by supporting the biochemical requirements of immunological effector functions and acting as a direct immunoregulatory signal from the TME itself. Despite this, neither cell-intrinsic nor environmental roles for metabolism in regulating TCE responses in solid tumors have been explicitly explored. We propose that metabolism is a powerful lens for understanding TCE efficacy and resistance in solid tumors, integrating signals from both surface receptors and the biochemical environment of the TME to shape T cell function and therapeutic response. In this mini-review, we highlight how three classical T cell signaling axes - 1) the T cell receptor complex, 2) costimulatory receptors, and 3) cytokine receptors - drive metabolic rewiring to license immune function and shape T cell fate. We also explore how environmental cues such as nutrients or metabolic stressors govern T cell responses, highlighting how biochemical perturbations within the TME could hamper TCE efficacy. Finally, we highlight emerging methods for dissecting metabolic contributions to TCE responses, proposing that understanding the interplay between immunological signaling, cellular metabolism, and immune programming could inform the design of next-generation TCEs for solid tumors.