It is increasingly appreciated that physical forces play important roles in cancer biology, in terms of progression, invasiveness, and drug resistance. Clinical progress in treating hematological malignancy and in developing cancer immunotherapy highlights the role of the hematopoietic system as a key model in devising new therapeutic strategies against cancer. Understanding mechanobiology of the hematopoietic system in the context of cancer will thus yield valuable fundamental insights that can information about novel cancer therapeutics. In this perspective, biophysical insights related to blood cancer are defined and detailed. The interactions with immune cells relevant to immunotherapy against cancer are considered and expounded, followed by speculation of potential regulatory roles of mesenchymal stromal cells (MSCs) in this complex network. Finally, a perspective is presented as to how insights from these complex interactions between matrices, blood cancer cells, immune cells, and MSCs can be leveraged to influence and engineer the treatment of blood cancers in the clinic.