Cancer cells are addicted to strong ribosome production to sustain their proliferation rate. Many chemotherapies impede ribosome production which is perceived by cells as "nucleolar stress" (NS), triggering TP53-dependent and independent response pathways leading to cell cycle arrest and/or apoptosis. The 5S RNP particle, a sub-ribosomal particle, is instrumental to NS response. Upon ribosome assembly defects, the 5S RNP accumulate as free form. This free form is able to sequester and inhibit MDM2, thus promoting TP53 stabilization. To investigate how cancer cells could resist to NS, we purified free-5S RNP and uncovered a new partner, SURF2. Functional characterization of this protein shows that SURF2 depletion increases cells sensitivity to NS, while its overexpression promotes their resistance to it. Consistently, SURF2 expression level negatively correlates with the overall survival in some cancers. Our data demonstrate that SURF2 can buffer free-5S RNP particles, and modulate their activity. SURF2 appears as a new regulator of NS response and a key player in both ribosomopathies and oncogenic mechanisms.