Biophysical modeling identifies an optimal hybrid amoeboid-mesenchymal mechanism for maximal T cell migration speeds.

Despite recent advances in cell migration mechanics, the principles governing rapid T cell movement remain unclear. Efficient migration is critical for antitumoral T cells to locate and eliminate cancer cells. To investigate the upper limits of cell speed, we develop a hybrid stochastic-mean field model of bleb-based cell motility. Our model suggests that cell-matrix adhesion-free bleb migration is highly inefficient, challenging the feasibility of adhesion-independent migration as a primary fast mode. Instead, we show that T cells can achieve rapid migration by combining bleb formation with adhesion-based forces. Supporting our predictions, three-dimensional gel experiments confirm that T cells migrate significantly faster under adherent conditions than in adhesion-free environments. These findings highlight the mechanical constraints of T cell motility and suggest that controlled modulation of tissue adhesion could enhance immune cell infiltration into tumors. Our work provides insights into optimizing T cell-based immunotherapies and underscores that indiscriminate antifibrotic treatments may hinder infiltration.