The concept of post-therapy metastatic spread, cancer repopulation and acquired tumor
cell resistance (M-CRAC) rationalizes tumor progression because of tumor cell heterogeneity arising
from post-therapy genetic damage and subsequent tissue repair mechanisms. Therapeutic strategies
designed to specifically address M-CRAC involve tissue editing approaches, such as low-dose
metronomic chemotherapy and the use of transcriptional modulators with or without targeted
therapies. Notably, tumor tissue editing holds the potential to treat patients, who are refractory to or
relapsing (r/r) after conventional chemotherapy, which is usually based on administering a maximum
tolerable dose of a cytostatic drugs. Clinical trials enrolling patients with r/r malignancies, e.g.,
non-small cell lung cancer, Hodgkin’s lymphoma, Langerhans cell histiocytosis and acute myelocytic
leukemia, indicate that tissue editing approaches could yield tangible clinical benefit. In contrast to
conventional chemotherapy or state-of-the-art precision medicine, tissue editing employs a multipronged
approach targeting important drivers of M-CRAC across various tumor entities, thereby,
simultaneously engaging tumor cell differentiation, immunomodulation, and inflammation control.
In this review, we highlight the M-CRAC concept as a major factor in resistance to conventional
cancer therapies and discusses tissue editing as a potential treatment.