## 1 Introduction  
The charged particle inverted dose-depth profile represents the physical pillar of protontherapy (PT), an advanced and rapidly spreading form of cancer radiotherapy (CRT) that makes use of high-energy (typically up to 230 MeV) accelerated proton beams to treat deep-seated tumours with elevated precision in dose deposition to the target volume [1,2]. The major benefit of PT resides in its greater sparing of normal tissue and/or organs at risk, compared to conventional CRT performed with photons/electrons. This in turn leads to a lower risk of adverse effects, most notably late-occurring radiation-induced secondary cancers [3]. Thus, PT is particularly attractive for pediatric cancers [4]. On the other hand, the low Relative Biological Effectiveness (RBE) exhibited by protons at the therapeutically useful energies [5] hinders, in principle, the treatment of radioresistant cancers by PT. In fact, tumour intrinsic or acquired radioresistance continues to represent a cause for failure in local tumour control, leading to recurrence, metastases and an overall poor prognostic outlook [6]. While unravelling existing uncertainties on proton radiobiology may lead to a re-assessment of both the clinical RBE used in PT, as well as of the cancer types eligible for PT [7,8], strategies aimed at potentiating proton biological efficacy are actively being sought [9,10]. In this context, [PERSON] et al. [11] proposed a novel binary approach termed Proton-Boron Capture Therapy (PBCT), based on the p + \({}^{11}\)B\(\rightarrow\)3\(\alpha\) (pB) nuclear reaction, which presents a maximum of the cross-section for proton energy of 675 keV and can generate short-range \(\alpha\)-particles that are densely ionizing, i.e., having a high Linear Energy Transfer (LET) [12]. This is poised to cause mainly unrepairable and highly localized DNA damage due to elevated lesion clustering along the alpha-particle tracks [13]. Using clonogenic cell death and FISH-labelled chromosome aberrations as radiobiological endpoints [14,15], experimental evidence supporting the feasibility of PBCT has been recently proven for the first time as the presence of the \({}^{11}\)B carrier BSH exacerbated the cytogenetic damage induced by therapeutic proton beams, which was attributed to the occurrence of the pB reaction triggered by low-energy protons across the Spread-Out Bragg Peak (SOBP) [16,17]. In fact, chromosome aberrations, a widely used indicator of the detrimental action at the DNA level by a variety of genotoxic insults [18], well reflect the energy deposition pattern at the nanometer scale and so-called complex-type rearrangements are peculiar to exposure to high-LET particles [19]. Thus, the fact that the frequency of this type of aberrations was maximum in the presence of BSH at the distal position of the SOBP [17] where protons' energy is the lowest across the SOBP, strongly argues for the high-LET \(\alpha\)-particles from the pB reaction as the effectors of PBCT. However, theoretical studies have predicted a much lower yield of such particles than that deemed sufficient to cause the reported radiobiological effects, questioning the actual role of the pB reaction [20,21]. We therefore performed for the first time cellular irradiations in the presence of \({}^{11}\)B with monochromatic proton beams having energy close to the reaction maximum cross-section to demonstrate the mechanistic rationale on which PBCT relies: If the pB reaction is indeed responsible for the radiobiological proton enhancement thus far reported, one may expect the greatest magnitude for such effects under these experimental conditions. The paucity of dedicated facilities where radiobiological experiments with low-energy protons can be carried out [22], made necessary to design and implement a novel cellular sample irradiation setup at an existing accelerator, the 3-MV Tandem Pelletron accelerator of the Center for Isotopic Research on the Cultural and Environmental Heritage (CIRCE) laboratory, Dept.