Differential effect of MTD versus low-dose metronomic (LDM) chemotherapy on CAF activation. In desmoplastic tumors, CAFs are especially abundant. Conventional MTD chemotherapy regimens can activate CAFs through increased activity of NF-κB and STAT1 transcription factors, which in turn causes the expression and release of ELR⁺ motif chemokines. These chemokines can bind to the chemokine receptor, CXCR2, expressed by tumor cells, causing a phenotypic conversion to TICs and increasing their relative numbers, thus paradoxically promoting malignant tumor progression. In contrast, by using an LDM chemotherapy regimen, CAFs are not activated or exhibit limited activation. Hence, a therapy-induced increase in TICs is not observed, while tumor growth is inhibited.