Table 1 Chemokine network in multiple myeloma

Pro-tumor

CCL2

CCR2

CCR4

When MM cells interact with macrophages, they trigger the expression of CCL2, which activates the JAK2/STAT3 pathway and increases MCPIP1 expression in macrophages. This helps to inhibit caspase activation in MM cells and encourages M2 polarization.

The CCL2-CCR2 axis prevents MM cells from apoptosis induced by chemotherapy drugs. CCL2 expression is likely to be tightly linked to treatment status.

Carlumab (tested in idiopathic pulmonary disease, pancreatic cancer, and solid tumors)

[15]

CCL3 (MIP-1α)

CCR1

CCR5

Elevated levels of CCL3 inhibit the expression of GATA1 and interfere with erythroid differentiation in CD34 + HSPCs via p38 signaling. Additionally, CCL3 elevates the expression of Bcl-2, Bcl-xl, and survivin while decreasing Bim expression, contributing to apoptosis resistance. The CCL3-CCR1 axis is linked to the migration of MM PCs from the bone marrow.

Blocking the CCL3-CCR1 pathway has the potential to alleviate anemia, bone disease, and the dissemination of MM tumors. It can also increase the effectiveness of melphalan and bortezomib in fighting MM and managing its progression.

AZD-4818 (tested in chronic obstructive pulmonary disease)

BI-638683 (tested safety)

BL5923 (tested in colon cancer and systemic lupus erythematosus)

BMS-817399 (tested in RA)

BX471

C-6448 (tested in MS)

C-4462 (tested in RA)

CCX9588, CCX721

CCX354 (tested in RA)

CP-481715 (tested in allergic contact dermatitis)

MLN-3701/MLN-3897

PS-031291/PS-375179 (discontinued)

UCB-35625 (tested in allergic inflammation and HIV-1)

J113863 (tested in arthritis)

[14, 18, 21, 50]

CXCL7

CXCR2

The processing of CXCL7 by MMP13 results in an increase in bioavailable CXCL7 and higher rates of osteoclast formation.

MMP13 activity is associated with reduced overall survival in tumor-bearing mice.

MMP13 inhibitors

[13]

CXCL8 (IL-8)

CXCR1

CXCR2

When MM-derived exosomes stimulated MSCs, they increased the secretion of IL-8, encouraging osteoclast function through the EGFR pathway. MM cells utilized MIF to induce the expression of IL-8 and IL-6 in BMSCs, but JQ1 was found to be effective in inhibiting cMYC, which helped to suppress this process.

Modulation of IL-8 is a possibility for therapeutic intervention in clinical practice.

CXCR1/2 inhibitor

CXCL8 mAb

AREG mAb

EGFR inhibitors (Gefitinib)

JQ1

[31, 34, 52]

CXCL12 (SDF-1)

CXCR4

CXCR7

Abnormal overexpression of CXCL12 is observed in cPCs, which results in its translocation into the bloodstream. The PI3K/PKB signaling pathway is responsible for upregulating IL-6 expression by CXCL12alpha, leading to reduced apoptosis of MM cells in the cell adhesion state. In addition, CXCL12gamma, immobilized to the membrane of BMSCs by HSPGs, facilitates MM cells’ adhesion to the stromal niche and promotes resistance against proteasome inhibitors.

CXCL12 contributes to the chemoresistance and adhesion of MM cells, while a low level of CXCR4 expression is associated with bortezomib resistance in MM.

Plerixafor

Olaptesed Pegol

Ruxolitinib

Copanlisib

Ulocuplumab

Motixafortide

F50067

[29, 30, 40,41,42, 53, 54]

CXCL13

CXCR5

CXCL13 is linked to the expression of RANKL in BMSCs and macrophages and the formation of osteoclasts. MM cells secrete CXCL13 to trigger M2 macrophage polarization and activate osteoclasts.

CXCL13 is associated with bone destruction, growth of tumors, and chemoresistance in MM

Ibrutinib

[28, 39]

Anti-tumor

CCL19

CCR7

The CAR-T cells that express IL-7 and CCL19 demonstrate excellent expansion, differentiation, migration, and durability. Moreover, the CCL19-CCR7 axis plays a crucial role in DC migration, and in MM, impaired CCR7 expression in Mo-DCs

decreases the migration of DCs.

CAR-T cells expressing IL-7 and CCL19 manifest safety and efficacy and are worthy of further clinical study.

SC-DCs with superior migration than Mo-DCs are potential candidates for cancer vaccines.

CAR-T cell immunotherapy

DC vaccine

[16, 26]

CXCL4 (PF-4)

CXCR3

Former research suggests PF-4 can induce MM cell apoptosis by upregulating SOCS3 expression to regress STAT3.

A lower serum level of PF-4 indicates poor overall survival.

-

[46]

Dual-effect

CCL5

CCR1

CCR3

CCR4

CCR5

CCL5 secreted by MDSC-inducible HMCLs is essential for MDSC induction in the myeloma microenvironment.

The CCL5-CCR5 axis can be intervened by immunomodulatory drugs acting on MM cells and PBMCs to prevent MDSC induction.

LEN

Pomalidomide

[22]

CXCL9

CXCL10

CXCR3

CXCR3 restrains IL-15-activated NK cells and anti-tumor efficacy from accumulating in the bone marrow.

Targeting CXCR3 can improve NK cell-dependent immunotherapy.

CXCR3 mAb

Eldelumab (Targeting CXCL10)

[55]

CXCL10 recruits CD8 + T cells and promotes proliferation rate, sensitivity, and cytolytic activity in targeting tumor cells.

Adding CXCL10 to CAR-T cells enhances anti-tumor efficacy, while its safety needs further clinical practice.

CAR-T cell immunotherapy

[17]