<p dir="ltr">Introduction: Radiotherapy is a treatment modality that is prescribed for more than 50% of cancer patients around the globe. Through decades of clinical application, RT has witnessed considerable advancements achieving significant tumor control with minimal damage to healthy tissues. Recently, a paradigm shift has recognized RT's potential to induce anti-tumor immune responses, where patients receiving radiation to the primary tumor also resolved lesions outside the treatment field. This out-of-field response also referred to as an abscopal effect, is believed to promote immunogenic cell death (ICD) initiated by the radiation-induced DNA damage and subsequent activation of the cGAS-STING-IFNβ pathways. However, clinical realization of an abscopal effect remains rare. We <i><u>hypothesize</u></i> by selectively irradiating cancer cells with high metastatic potential within a solid tumor (intra-tumor radiotherapy treatment planning) with high metastatic potential, a more efficient anti-tumor response can be achieved while minimizing inflammatory responses from surrounding tumor and normal tissues, obfuscating a potential adaptive immune response, thus help in overcoming the rarity observed in the clinical practice. To achieve this <i><u>objective</u></i>, radiotherapy treatment plans targeting hypoxic regions (known to harbor a metastatic phenotype) within a solid tumor and optimally activating IFNβ will be investigated.</p><p dir="ltr">Methods: Hypoxic conditions within tumor microenvironments significantly reduce DNA damage, conferring a radioresistant phenotype that leads to RT failure. To address the inherent radioresistance and immunosuppression of hypoxic tumors, high linear energy transfer (LET) modalities are used. Our research aims to enhance the specificity and efficiency of ICD, particularly in highly metastatic (hypoxic) regions within the tumor, by employing heavy charged particle (HCP) beams to optimize DSB induction. Empirical mathematical models have been developed to predict the dose-response of IFNb based on in vitro data and Monte Carlo methods of DSB-induction. These methods are used in maximizing type I interferon (IFNβ) production and subsequent immune response while minimizing the inflammatory response and damage to surrounding tissue. Immunogenic treatment plans, iTPS, have been developed to integrate charged particle beam models for proton, helium, and carbon ions and the above-empirical models into FLUKA Monte Carlo simulations and subsequently evaluated in clinical case studies of brain and lung cancer. Next, new biophysical models accounting for tumor hypoxia were developed and integrated into the iTPS, and clinical case studies were reevaluated.</p><p dir="ltr">Results: SA(1): Developed and integrated charged particle beam models into FLUKA MC for both homogeneous and heterogeneous treatment planning. Empirical equations for RBE_{DSB, pO2}, LET, and IFNβ dose-response were incorporated into FLUKA for voxel-based simulations across oxygen levels. SA(2): RBE_DSB-weighted optimization yielded uniform IFNβ production. High LET enabled carbon ion beams to require the lowest doses, achieving superior peak-to-entrance ratios of 15.85 compared to 10.78 and 7.60 for helium and proton beams, respectively. Patient simulations demonstrated carbon ions' superiority, with D_95% values of 7.68 Gy for the brain and 7.60 Gy for lung tumors, excelling in IFNβ production. SA(3): An optimized treatment plan for uniform IFNβ in hypoxia utilizing empirical equations for RBE_DSB across hypoxia levels was created for different charged particles. MCC13 adjustments based on OER_DSB from MCDS were confirmed by measured data in U251 cell lines, showing an OER of 1.5 between normoxia and 1% hypoxia, closely matching MCDS predictions within a 7% discrepancy. Carbon ions achieved optimal IFNβ at 11.02 Gy for brain tumors under 0.1% hypoxia in FLUKA simulations.</p><p dir="ltr">Conclusions: Our results from both homogeneous target and patient cases demonstrate that charged particles have the potential to elicit higher levels of IFNβ at lower doses compared to photon irradiations in different pO₂ levels. High LET irradiation not only ensures a highly localized IFNβ response in the target but also effectively spares surrounding normal tissues, thereby minimizing treatment-related toxicity. This finding underscores the superiority of high LET irradiation in achieving targeted immunogenic effects while enhancing the therapeutic window by reducing damage to normal cells.</p>