Cytotoxic lymphocytes can migrate rapidly and with striking versatility in a continuous search for cells to subdue. Adoptive cell transfer immunotherapies attempt to harness the capacity of T cells and natural killer (NK) cells to effectively locate, engage and kill cancer targets, yet they have thus far largely proved unsuccessful when targeting solid malignancies, chiefly due to insufficient tumour infiltration. Moreover, the mechanisms and cellular forces that underpin the coordinated movements and interactions of killer immune cells and tumour cells are incompletely understood. Here, we investigate the intercellular signalling and mechanical forces that these killer immune cells employ to effectively infiltrate and attack solid tumour cells. Using an integrative and multidisciplinary method encompassing cell and cancer biology, immunology, advanced live-cell microscopy, image analysis, biophysics, and modelling, we are uncovering the intricate mechanobiology of cytotoxic lymphocyte-mediated tumour rejection.