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

Despite recent advances in understanding 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 developed a hybrid stochastic-mean field model of bleb-based cell motility. Our model demonstrates that cell-matrix adhesion-free bleb-based migration is highly inefficient, challenging the feasibility of cell swimming/adhesion-independent migration as a primary motility mode. Instead, we show that T cells can achieve rapid migration by combining bleb formation with adhesion-based forces. Supporting our predictions, our 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 modifying tissue adhesion properties in a controlled manner could enhance immune cell infiltration into tumors. Our computational and experimental work provides insights for optimizing T cell-based immunotherapies. While antifibrotic treatments could alter the tumor microenvironment, indiscriminate reduction of adhesion may not be ideal for T cell infiltration and motility, highlighting the need for targeted antifibrotic strategies.