CXCL3 is a chemokine that functions as a ligand for CXCR2 and plays a critical role in neutrophil recruitment and inflammatory responses. The processed form of CXCL3 exhibits particularly potent chemotactic activity for neutrophilic granulocytes. CXCL3 operates through the CXCL3/CXCR2 axis to orchestrate immune cell infiltration in diverse pathological contexts. In colorectal cancer, the microbial metabolite 4-hydroxybenzeneacetic acid activates the JAK2/STAT3 pathway to upregulate CXCL3, driving recruitment of immunosuppressive PMN-MDSCs and enabling resistance to anti-PD-1 immunotherapy; selective CXCL3 knockdown resensitized tumors to checkpoint blockade 1. In pancreatic cancer, IL-33-stimulated macrophages upregulate CXCL3, which activates CXCR2 on cancer-associated fibroblasts to promote a myofibroblastic phenotype that facilitates metastasis, and elevated CXCL3 correlates with poor survival in patients with pancreatic ductal adenocarcinoma 2. In breast cancer, IL1β+CXCL3+ CD4+ T cells secrete CXCL3 to sustain neutrophil infiltration and promote neutrophil ferroptosis, which suppresses antitumor immunity and drives chemoresistance 3. Similarly, in colorectal cancer, oncogenic KRAS represses IRF2, which normally suppresses CXCL3; elevated CXCL3 recruits MDSCs and confers resistance to anti-PD-1 therapy that can be overcome by CXCR2 inhibition 4. Beyond cancer, CXCL3 participates in aortic dissection progression through the CXCL3/CXCR2 axis, which orchestrates neutrophil extracellular trap formation 5, and appears in rheumatoid arthritis synovium where it is upregulated in NF-κB signaling 6. Therapeutic targeting of CXCR2 represents a promising strategy to reverse the immunosuppressive tumor microenvironment and restore immunotherapy efficacy.