Abstract / Summary
Circulating neutrophils are the most abundant leukocyte subset, yet their role in tumor progression is far more intricate than previously assumed. Neutrophils were historically viewed as short-lived effectors of innate immunity—mobilized transiently during acute inflammation and deemed largely irrelevant to chronic tumorigenesis—but this simplistic perspective has been upended by mounting evidence revealing them as a profoundly heterogeneous population. Distinct subsets can exert diametrically opposed effects, either constraining or fueling malignant growth. Within the tumor microenvironment (TME), specific neutrophil populations acquire potent immunosuppressive traits that not only shield tumors from immune surveillance but also undermine the efficacy of checkpoint blockade therapies. In this review, we trace the developmental origins of these suppressive neutrophils and draw upon recent single-cell transcriptomic studies to delineate their striking phenotypic diversity. We further dissect the molecular circuitry through which they suppress anti-tumor immunity, explore whether neutrophil-derived gene signatures can serve as reliable predictors of response to immunotherapy, and evaluate emerging therapeutic strategies. These approaches aim to block neutrophil recruitment, reprogram their functional polarization, or neutralize their suppressive activity in combination with checkpoint inhibitors. Deciphering the cues that drive neutrophils toward an immunosuppressive state will be pivotal in designing next-generation immunotherapy regimens capable of overcoming neutrophil-mediated resistance across a broad spectrum of cancers.