Here we show that (i) among all subtypes of BC, PTX3 is highly expressed in the most aggressive TNBC subtype, (ii) the main source of PTX3 in TNBC patient-derived samples is represented by tumor cells rather than the stromal/immune component, and (iii) PTX3 expression by tumor cells fosters the tumorigenic potential of TNBC by activating a PTX3/TLR4 autocrine loop. Here, TLR4 is linked to breast cancer.