Table 1.

Stresses and stress mitigation pathways that can limit therapeutic activity.

Endogenous and therapeutic stresses	Master regulators of stress mitigation pathways	Stress mitigation pathways	Examples of therapeutic response affected by stress mitigation pathways	Ref
Metabolic	AMPK, SIRT1, mTOR, PHD/HIF system	Oxphos/Glycolysis balance, autophagy, mitophagy, mitochondial metabolism, lipid metabolism	Metformin, BRAFi, phenformin	73,201,202
Oxidative	NRF2, NF-kB, HIF1	Antioxidant programs, metabolic reprograming	Radiation therapy, temozolomide, gemcitabine	77,203–205
Apoptosis	p53, TRAIL	BCL2 family balance, epithelial to mesenchymal transition, senescence phenotype	Doxorubicin, paclitaxel, BCL2i, BCL2/XLi, radiation therapy	206–209
Endoplasmic reticulum/proteostatic	GRP78, PERK, IRE1a, ATF6	Unfolded protein response, E-Rassociated degradation, heat shock response, proteasome upregulation, autophagy	Chemotherapy, tamoxifen, multi-RTKi	210
Hypoxia	HIFs	Hypoxic response, angiogenesis, metabolic reprograming, autophagy, extracellular matrix remodelling, immune suppression	anti-VEGFR, multi-RTKi	211–213
DNA damage/replication stress	ATM, ATR, CHK1, CHK2, RPA, H2AX	Cell cycle checkpoints, DNA repair, anti-apoptotic response, replication stress response	Gemcitabine, PARPi, doxorubicin, cisplatin, radiation therapy,	214–216
Immune activation	Sting, STAT3, TGFb	Reduced antigen presentation, immune checkpoint activation	Radiation therapy, PARPi, anti-PD1, anti-PD-L1	68,217,218