Nuclear mechanobiology plays key roles in regulating cell responses1–31. A. Kumar, J. K. Placone, and A. J. Engler, “ Understanding the extracellular forces that determine cell fate and maintenance,” Development 144(23), 4261–4270 (2017). https://doi.org/10.1242/dev.1584692. H. Huang, R. D. Kamm, and R. T. Lee, “ Cell mechanics and mechanotransduction: Pathways, probes, and physiology,” Am. J. Physiol. Cell Physiol. 287(1), C1–11 (2004). https://doi.org/10.1152/ajpcell.00559.20033. D. E. Discher, P. Janmey, and Y. L. Wang, “ Tissue cells feel and respond to the stiffness of their substrate,” Science 310(5751), 1139–1143 (2005). https://doi.org/10.1126/science.1116995 in many cell types. For example, Jain et al. focused on macrophages, noting key changes in their activation and dynamic signaling that result from the exposure of cells to micropatterned surfaces, stiff substrates, and high forces.3232. N. Jain, J. M. Lord, and V. Vogel, “ Mechanoimmunology: Are inflammatory epigenetic states of macrophages tuned by biophysical factors?,” APL Bioeng. 6(3), 031502 (2022). https://doi.org/10.1063/5.0087699 These findings raise the intriguing possibility that physical cues from the microenvironment, in addition to the established chemical cues, can modulate specific immune responses. Nucleus-based mechanisms were critical in these responses, e.g., nuclear translocation of transcription factors, epigenetic modifications, and even DNA methylation. Insights such as these will continue to deepen our understanding of how the nucleus regulates cell behavior, and, in turn, how the physical world around the nucleus shapes it. Yet, many gaps remain in our understanding of mechanobiology's implications, not just in macrophages, but in all aspects of life, begging further study of these structures, methods, and applications. For example while forces are transmitted to the nucleus,3333. K. V. Iyer, S. Pulford, A. Mogilner, and G. V. Shivashankar, “ Mechanical activation of cells induces chromatin remodeling preceding MKL nuclear transport,” Biophys. J. 103(7), 1416–1428 (2012). https://doi.org/10.1016/j.bpj.2012.08.041 the following remain to be elucidated: (i) how those forces are transmitted to the nucleus, (ii) how they alter chromatin organization, (iii) how they increase expression of specific genes, and (iv) how nuclear mechanotransduction—including through the nuclear membranes, nuclear pores, and chromatin—is coordinated with cytoplasmic mechanotransduction processes. While many other systems beyond macrophages are known to be influenced by nuclear mechanotransduction, e.g., muscular dystrophy1616. A. J. Earle, T. J. Kirby, G. R. Fedorchak, P. Isermann, J. Patel, S. Iruvanti, S. A. Moore, G. Bonne, L. L. Wallrath, and J. Lammerding, “ Mutant lamins cause nuclear envelope rupture and DNA damage in skeletal muscle cells,” Nat. Mater. 19(4), 464–473 (2020). https://doi.org/10.1038/s41563-019-0563-5 and dilated cardiomyopathy,3434. P. M. Davidson, G. R. Fedorchak, S. Mondesert-Deveraux, E. S. Bell, P. Isermann, D. Aubry, R. Allena, and J. Lammerding, “ High-throughput microfluidic micropipette aspiration device to probe time-scale dependent nuclear mechanics in intact cells,” Lab Chip 19(21), 3652–3663 (2019). https://doi.org/10.1039/C9LC00444K our understanding of how forces impact gene expression remains limited. Additional insights are required to understand how altered nuclear mechanotransduction and/or increased nuclear fragility contribute to tissue specific phenotypes and to develop effective treatment approaches for these devastating diseases, providing further motivation for continued advances in nuclear mechanobiology.