Introduction: Neutrophils or polymorphonuclear cells (PMNs) account for a considerable portion of the tumor immune stroma. Emerging single-cell transcriptomic analyses have elucidated the striking cellular heterogeneity of PMNs during homeostasis and pathologic conditions and have established their diverse roles in cancer. PMNs have emerged as important players in cancer pathobiology and therapeutic resistance. Tumor-associated neutrophils (TANs) effector functions influence tumor development and resistance or response to therapy.

Areas covered: This review focuses on PMN heterogeneity and functional diversity in the context of carcinogenesis. TANs, by activating diverse signaling pathways, contribute to cancer progression and resistance to therapies. Mechanisms by which TANs impact therapeutic resistance include alterations of the tumoral DNA damage response, angiogenesis, reactivation of cancer dormancy, enhancement of tumor cell proliferation/survival and immune evasion.

Expert opinion: With the emerging phenotypic and function heterogeneity of TANs, targeting specific TAN functions in developing tumors can lead to translatable therapeutic approaches and limit drug resistance. We propose that combining specific targeting of TAN activity with standard cancer therapy can help patients achieving a complete response and prevent cancer relapse.