Eradicating Cancer Stem Cells Using High Linear Energy Transfer Radiation Therapy Part 2: LET Painting and Other Advanced Techniques

Abstract Linear energy transfer (LET), a measurement of ionization density, tracks the radiobiological potency of any given course of therapeutic radiation and its efficacy in killing cancer cells. As opposed to the low LET of photon and proton therapy, high LET charged particle therapy can overcome multiple mechanisms of resistance to effectively treat radioresistant tumors. A robust basic science literature demonstrates enhanced direct cancer stem cell (CSC) sterilization with increasing LET along with indirect mechanisms of tumor control such as immunogenesis. Such a strategy has yet to be implemented in clinical practice in the absence of an effective means of targeting CSCs without risking unacceptable harms to patients. In Part 2 of this 2-part series, we review newly emergent functional imaging technologies in conjunction with existing techniques of spatial fractionation and capabilities for multi-ionic therapy that hold promise as a means of translating the biological potential of high LET therapy into clinical protocols for effective anti-CSC therapy.