Table 1 The underlying mechanisms and dual roles of mitochondrial ROS stress in the tumor microenvironment

MAPK cascades/ ERK1/2/ JNKs/p38

√

Proliferation, survival, migration

[17,18,19, 81]

Mn-SOD / antioxidant

√

Antioxidative system

[29, 30, 112, 113]

GSH/ antioxidant

√

Antioxidative system

[31, 32]

NF-κB

√

Cytokines/Inflammatory response

[81]

TGF-β

√

Tumorigenesis/ Inflammatory response

[81, 87,88,89,90,91,92,93,94]

Mitophagy/NIX/BNIP3

√

Cell survival/dysfunctional mitochondria removal/ anti-apoptosis

[261, 292,293,294,295]

Mitophagy/PINK-Parkin

√

Cell survival

[120, 121]

Hsp60 /mtHsp70/Mitochondrial chaperones

√

Protein refolding/UPRmt Proliferation and metastasis

[57,58,59,60,61,62, 82]

Lon/Mitochondrial chaperones

√

Elevated mtROS/ tumorigenesis

[48, 79,80,81,82,83,84,85]

Intracellular Ca²⁺ increasing under hypoxia

√

ROS generation /tumorigenesis/ drug resistance

[84, 95, 101,102,103,104,105,106, 108, 296]

Increasing Ca²⁺ in mitochondria

√

Cytochrome C releasing/apoptosis

[95, 96, 109]

p53

√

Apoptosis

[83, 293]

Autophagy

√

√

ROS suppression/ Cell survival /Cell death

[35]

PTEN

√

Neutralizes intracellular ROS/immune escape

[297]

PD-L1

√

Immune resistance

[131, 141, 219]

STAT3

√

Inflammatory response/IL-6

[84, 138]

HIF-1

√

ROS generation/ Cell survival/ Tumorigenesis

[121, 123, 150,151,152]

mtDNA oxidation/damage

√

√

ROS generation/Cell death/ Inflammation/ Drug resistance

[131, 156,157,158,159, 212,213,214, 298, 299]

Cisplatin-induced mtDNA damage

√

ROS generation/ Cell death/ Ca²⁺-dependent cisplatin resistance

[84, 96, 156, 222, 263]

Immune cells

PD-1/PD-L1

√

Immune inhibition

[141]

CD39/CD73

√

Immune evasion of T cell

[144, 145]

TCR/CD8-MHC

√

Immune suppression of T cell

[146]

Arginase-1/nitric oxide /peroxynitrite

√

Inhibit T cells proliferation

[147,148,149]

Fas

√

T cell apoptosis

[164]

IL-15

√

NK cells resistance against oxidative stress

[163]

DAMPs/HMGB1

√

DC activation and ultimately

antitumor T cell responses

[166,167,168]

NOX2

√

Myeloid cell ROS production

[169]

Thioredoxin-1

√

Antioxidative function for regulatory T cells

[171, 172]

Glutathione

√

Restricting serine metabolism to preserve Treg function

[173]

M1 macrophage signaling pathway

√

Tumor suppression

[179, 180, 199]

M2 macrophage polarization

√

Promote tumor progressions

[81, 182, 183, 199, 300]

IL-6

√

Tumor-associated macrophage differentiation [TAM]

[185, 186]

Proinflammatory cytokines, or TLR ligands, LPS, IL-6

√

Mature DCs drive effector T cell response

[190]

IL-10, TGF-β, Vit-D3

√

Regulatory DCs [regDCs] dampen effector T cell differentiation or activate Tregs

[190]

Oxidatively truncated lipid bodies in DCs

√

Deaden CD8 T cells responses

[301]

Ebselen

√

Inhibits ROS production, DC-T cell cross talk for cytokine production

[204]

mtROS elevation

√

Obstructed antigen presentation disrupt DCs/T cell

[205]

ROS-triggered ER stress

√

Inhibition of IL-1β, CD86, and IL-12 in DCs to inhibit effective T cells

[302]