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

The authors describe advanced high linear energy transfer (LET) techniques, including LET painting, biologically guided spatial fractionation, and multi-ion therapy, as potential methods to selectively ablate cancer stem cells while sparing normal tissue. The article highlights recent imaging advances that could help define high-risk tumor subvolumes and outlines logistical and clinical challenges to widespread implementation, making a compelling case for heavy particle therapy as a means of augmenting systemic cancer control.

Upon completing this activity:

• Clinicians will be able to discuss the principles of LET painting and multi-ion heavy particle therapy as emerging strategies to selectively target cancer stem cell–rich tumor subvolumes.

• Clinicians will be prepared to utilize functional imaging modalities to target both hypoxia and the underlying biological properties of cancer stem cells.

• Clinicians will be able to incorporate PATHY and grid/lattice spatial fractionation techniques into clinical practice while understanding the relative advantages and disadvantages of each approach.

Daniel M. Koffler, MD¹; Daniel K. Ebner, MD, MPH²; Eric J. Lehrer, MD², Fatemeh Fekrmandi, MD³; Felix Ehret, MD^4,5; Morteza Mahmoudi, PhD⁶; Chris Beltran, PhD¹; Daniel M. Trifiletti, MD¹; Laura Vallow, MD¹; Michael S. Rutenberg, MD, PhD¹; Jacob Eckstein, MD⁷; Bhargava Chitti, MD⁸; Bryan Johnson, MD¹; Joseph M. Herman, MD⁸; Walter Tinganelli, PhD⁹

• Radiation oncologists

• Related oncology professionals

None

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Institute for Advanced Medical Education (IAME) and Anderson Publishing. IAME is accredited by the ACCME to provide continuing medical education for physicians. IAME designates this activity for a maximum of 2 AMA PRA Category 1 Credit^™ . Physicians should claim only the credit commensurate with the extent of their participation in the activity.

1. Review this article in its entirety.

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4. Complete the post test and review the discussion and references.

5. Complete the evaluation.

6. Print your certificate.

June 25, 2026

The authors disclose no relationships with ineligible companies.

IAME has assessed conflicts of interest with its faculty, authors, editors, and any individuals who were in a position to control the content of this CME activity. Any relevant financial relationships were mitigated with an independent peer review of this activity, and no conflicts or commercial bias were detected. IAME’s planners, content reviewers, and editorial staff disclose no relationships with ineligible entities.