Fusion protein-mediated costimulation in engineered T cells: from intrinsic signaling to tumor microenvironment rewiring.

Adoptive T cell therapies have markedly improved outcomes in hematologic malignancies but their efficacy in solid tumors can be diminished by a hostile tumor microenvironment that impedes sustained therapeutic responses. Beyond challenges such as limited trafficking and antigen heterogeneity, engineered T cells face suppressive myeloid and stromal populations, inhibitory checkpoint ligand interactions, and metabolically hostile niches that collectively diminish effector function and persistence. To overcome these barriers, a new generation of fusion protein-based costimulatory strategies has emerged that couple ligand-guided sensing of the tumor microenvironment with modular control of T cell activation and fate. This review examines how conventional and non-canonical costimulatory modules, when incorporated into chimeric antigen receptor (CAR) and T cell receptor (TCR) architectures, modulate T cell differentiation and function within the tumor site. It further analyzes how membrane-anchored and secreted fusion proteins enable engineered T cells to activate dendritic cells, reprogram myeloid cells, and convert poorly inflamed tumors into treatment-responsive environments. Together, these advances establish a design framework in which fusion protein-based receptors and ligands enhance T cell function and remodel the tumor microenvironment, thereby expanding the therapeutic potential of adoptive T cell therapy for solid tumors.