Therapy-induced microenvironmental senescence in tumor treatment resistance: From mechanism to therapy

Tumor microenvironment with high complexity and heterogeneity is one of the hallmarks of tumor and a key driver of treatment resistance. Conventional antitumor therapies, such as chemotherapy and radiotherapy, trigger tumor cell senescence through mechanisms involving DNA damage and oxidative stress. These senescent tumor cells, in turn, promote tumor malignancy via the senescence-associated secretory phenotype (SASP), thereby facilitating treatment resistance. Accumulating evidence indicates that, in addition to tumor cells, various microenvironmental components including endothelial cells, immune cells, and fibroblasts also undergo senescence in response to chemo- and radiotherapeutic stress. This prevalent therapy-induced microenvironmental senescence remodels the tumor microenvironment and fuels treatment resistance, highlighting its potential as a target for combination therapy. In this review, we outline the mechanisms underlying therapy-induced tumor cell senescence, with a particular emphasis on the mechanisms by which therapy-induced senescence of major non-tumoral components within tumor microenvironment mediates therapy resistance. Furthermore, we summarize the current therapeutic strategies targeting therapy-induced senescence, aiming to provide novel insights into the rational combination of senescence-targeted therapies with conventional radiotherapy and chemotherapy for tumor treatment.