Taking a Full Snapshot of Cancer Biology: Deciphering the Tumor Microenvironment for Effective Cancer Therapy in the Oncology Clinic.

A bottleneck that is hindering therapeutics innovation in cancers is the current lack of integration of what we have learned in tumor biology as well as the tumor microenvironment (TME). This is because tumors are complex tissues composed of cancer cells, stromal cells, and the extracellular matrix (ECM). Although genetic alterations might cause the initial uncontrolled growth, resistance to apoptosis in cancer cells and stromal cells play additional key roles within the TME and thus influence tumor initiation, progression, therapy resistance, and metastasis. Therapies targeting cancer cells are usually insufficient when the stromal component of the TME causes therapy resistance. For innovation in cancer treatment and to take a full snapshot of cancer biology, anticancer drug design must, therefore, target both cancer cells and the stromal component. This expert review critically examines the TME components such as cancer-associated fibroblasts and ECM that can be reprogrammed to create a tumor-suppressive environment, thereby aiding in tumor treatment. Better cancer experimental models that mimic the TME such as tumor spheroids, microfluidics, three dimensional (3D) bioprinted models, and organoids will allow deeper investigations of the TME complexity and can lead to the translation of basic tumor biology to effective cancer treatments. Ultimately, innovative cancer treatments and, by extension, improvement in cancer patients' outcomes will emerge from combinatorial drug development strategies targeting both cancer cells and stromal components of the TME. Combinatorial treatment strategies can take the form of chemotherapy and radiotherapy (targeting tumor cells and stromal components) and immunotherapy that is able to regulate immune responses against tumor cells. This expert review thus addresses a previously neglected knowledge gap in cancer drug design and development by broadening the focus in cancer biology to TME so as to empower disruptive health care innovations in the oncology clinic.