Effective Tumor Destruction Research Articles

Pitaya-Inspired Metal-Organic Framework Nanozyme for Multimodal Imaging-Guided Synergistic Cuproptosis, Nanocatalytic Therapy, and Photothermal Therapy.

Nature often provides invaluable insights into technological innovation and the construction of nanomaterials. Inspired by the pitaya fruit's strategy of wrapping seeds within its pulp to enhance seed survival, a unique nanocomposite based on metal-organic framework (MOF)-encapsulated CuS nanoparticles (NPs) is developed. This design effectively addresses the challenge of short retention time afforded by CuS NPs for therapeutic and imaging purposes. The MOF acts as the "pitaya pulp" protecting the internal CuS NPs ("pitaya seeds"), thereby increasing their retention time in vivo. This system exhibits triple-enzyme-mimicking activities and is proposed for application in photoacoustic and magnetic resonance imaging-guided therapies, including chemodynamic therapy, photothermal therapy, and cuproptosis-related therapy. The exceptional enzyme-mimicking activities of superoxide dismutase, catalase, and peroxidase not only produce oxygen to alleviate hypoxia but also generate a reactive oxygen species (ROS) storm for effective tumor destruction. By combining these multienzymatic properties, superior photothermal performance, and Cu-induced cuproptosis, nanozyme-treated mice exhibited an 84% inhibition of tumor growth-approximately double the effect observed in mice treated with CuS NPs alone. This study presents a smart strategy for integrating imaging with therapeutic modalities, achieving exceptional outcomes for precise imaging-guided tumor therapy.

Synergistic Enhancement of Photodynamic Cancer Therapy with Mesenchymal Stem Cells and Theranostic Nanoparticles.

Nanoparticles engineered to combat cancer and other life-threatening diseases may significantly improve patient outcomes. However, inefficient nanoparticle delivery to tumors limits their use and necessitates the development of complex delivery approaches. Here, we examine this issue by harnessing the tumor-homing abilities of human mesenchymal stem cells (MSCs) to deliver a decoupled theranostic complex of rare earth-doped nanoparticles (dNPs) and photosensitizer chlorin e6 (Ce6) to tumors. We show that both bone-marrow- and skin-derived MSCs can transport the dNP-Ce6 complex inside tumor spheroids, which is challenging to accomplish by passive delivery alone. MSCs deliver the dNP-Ce6 complex across the tumor spheroid, facilitating more effective photodynamic damage and tumor destruction than passively accumulated dNP-Ce6. The dNP-Ce6 complex also provides the built-in ability to monitor the MSC migration without causing undesired phototoxicity, which is essential for maximal and side-effect-free delivery of nanoparticles. Our results demonstrate how MSCs can be used as delivery vehicles for the transportation of the dNP-Ce6 complex, addressing the limitations of passive nanoparticle delivery and providing light-based theranostics.

Fasting-Mimicking Diet Facilitates Anti-tumor Therapeutic Effects by Nutrient-Sensitive Nanocomposites.

Cancer cells support their uncontrolled proliferation primarily by regulating energy metabolism. Inhibiting tumor growth by blocking the supply of nutrients is an effective treatment strategy. Fasting-mimicking diet (FMD), as a low-calorie, low-protein, low-sugar, high-fat diet, can effectively reduce the nutrient supply to tumor cells. However, the significant biological barrier presented by the tumor microenvironment imposes greater demands and challenges for drug design. This study constructs the multifunctional nanocomposite ZnFe2O4@TiO2@CHC@Orl-FA (ZTCOF), which has great potential to overcome the aforementioned drawbacks. ZnFe2O4@TiO2 could produce 1O2 with ultrasound, and stimulate the Fenton-like conversion of endogenous H2O2 to ·OH, achieving a combined therapeutic effect of sonodynamic therapy (SDT) and chemodynamic therapy (CDT). Orl (Orlistat) and CHC (α-cyano-4-hydroxycinnamic acid) not only block tumor cell energy metabolism but also increase sensitivity to reactive oxygen species, enhancing the cytotoxic effect on tumor cells. Furthermore, combining the treatment strategies with FMD condition control can further inhibit cancer cell energy metabolism, achieving significant synergistic anti-tumor therapy. Both in vitro and in vivo experiments confirm that ZTCOF with SDT/CDT/starvation can achieve effective tumor suppression and destruction. This work provides theoretical and technical support for anti-tumor multimodal synergistic therapy.

Bioorthogonal Cu Single-Atom Nanozyme for Synergistic Nanocatalytic Therapy, Photothermal Therapy, Cuproptosis and Immunotherapy.

Single-atom nanozymes (SAzymes) with atomically dispersed active sites are potential substitutes for natural enzymes. A systematic study of its multiple functions can in-depth understand SAzymes's nature, which remains elusive. Here, we develop a novel ultrafast synthesis of sputtered SAzymes by in situ bombarding-embedding technique. Using this method, sputtered copper (Cu) SAzymes (CuSA) is developed with unreported unique planar Cu-C3 coordinated configuration. To enhance the tumor-specific targeting, we employ a bioorthogonal approach to engineer CuSA, denoted as CuSACO. CuSACO not only exhibits minimal off-target toxicity but also possesses exceptional ultrahigh catalase-, oxidase-, peroxidase-like multienzyme activities, resulting in reactive oxygen species (ROS) storm generation for effective tumor destruction. Surprisingly, CuSACO can release Cu ions in the presence of glutathione (GSH) to induce cuproptosis, enhancing the tumor treatment efficacy. Notably, CuSACO's remarkable photothermal properties enables precise photothermal therapy (PTT) on tumors. This, combined with nanozyme catalytic activities, cuproptosis and immunotherapy, efficiently inhibiting the growth of orthotopic breast tumors and gliomas, and lung metastasis. Our research highlights the potential of CuSACO as an innovative strategy to utilize multiple mechanism to enhance tumor therapeutic efficacy, broadening the exploration and development of enzyme-like behavior and physiological mechanism of action of SAzymes.

Bioorthogonal Cu Single‐Atom Nanozyme for Synergistic Nanocatalytic Therapy, Photothermal Therapy, Cuproptosis and Immunotherapy

AbstractSingle‐atom nanozymes (SAzymes) with atomically dispersed active sites are potential substitutes for natural enzymes. A systematic study of its multiple functions can in‐depth understand SAzymes's nature, which remains elusive. Here, we develop a novel ultrafast synthesis of sputtered SAzymes by in situ bombarding‐embedding technique. Using this method, sputtered copper (Cu) SAzymes (CuSA) is developed with unreported unique planar Cu‐C3 coordinated configuration. To enhance the tumor‐specific targeting, we employ a bioorthogonal approach to engineer CuSA, denoted as CuSACO. CuSACO not only exhibits minimal off‐target toxicity but also possesses exceptional ultrahigh catalase‐, oxidase‐, peroxidase‐like multienzyme activities, resulting in reactive oxygen species (ROS) storm generation for effective tumor destruction. Surprisingly, CuSACO can release Cu ions in the presence of glutathione (GSH) to induce cuproptosis, enhancing the tumor treatment efficacy. Notably, CuSACO′s remarkable photothermal properties enables precise photothermal therapy (PTT) on tumors. This, combined with nanozyme catalytic activities, cuproptosis and immunotherapy, efficiently inhibiting the growth of orthotopic breast tumors and gliomas, and lung metastasis. Our research highlights the potential of CuSACO as an innovative strategy to utilize multiple mechanism to enhance tumor therapeutic efficacy, broadening the exploration and development of enzyme‐like behavior and physiological mechanism of action of SAzymes.

Mg-ZIF nanozymes disrupt the level of ROS for osteosarcoma killing via POD activity.

Osteosarcoma (OS) is notorious for its high malignancy, and conventional chemotherapy drugs, while killing tumor cells, often inflict significant harm on the patient's body. The tumor microenvironment of OS is characterized by high levels of hydrogen peroxide (H2O2). Leveraging this feature, we have developed Mg-ZIF nanoparticles, which incorporate magnesium (Mg) to confer robust peroxidase (POD)-like enzymatic activity. These Mg-ZIF nanozymes can generate highly lethal superoxide anions within tumor cells in a responsive manner, thereby achieving effective tumor destruction. Both in vitro and in situ OS models have corroborated the anti-tumor efficacy of Mg-ZIF nanozymes, while also validating their biosafety. The design of Mg-ZIF nanozymes opens a new avenue for the treatment of OS, offering a promising therapeutic strategy.

Antitumor Effects of Carrier-Free Functionalized Lignin Materials on Human Hepatocellular Carcinoma (HepG2) Cells.

Lignin, as an abundant aromatic biopolymer in plants, has great potential for medical applications due to its active sites, antioxidant activity, low biotoxicity, and good biocompatibility. In this work, a simple and ecofriendly approach for lignin fractionation and modification was developed to improve the antitumor activity of lignin. The lignin fraction KL-3 obtained by the lignin gradient acid precipitation at pH = 9-13 showed good cytotoxicity. Furthermore, the cell-feeding lignin after additional structural modifications such as demethylation (DKL-3), sulfonation (SL-3), and demethylsulfonation (DSKL-3) could exhibit higher glutathione responsiveness in the tumor microenvironment, resulting in reactive oxygen species accumulation and mitochondrial damage and eventually leading to apoptosis in HepG2 cells with minimal damage to normal cells. The IC50 values for KL-3, SL-3, and DSKL-3 were 0.71, 0.57, and 0.41 mg/mL, respectively, which were superior to those of other biomass extractives or unmodified lignin. Importantly, in vivo experiments conducted in nude mouse models demonstrated good biosafety and effective tumor destruction. This work provides a promising example of constructing carrier-free functionalized lignin antitumor materials with different structures for inhibiting the growth of human hepatocellular carcinoma (HepG2) cells, which is expected to improve cancer therapy outcomes.

NSAIDs-induced oxidative stress sensitizes tumor cells to T cell cytotoxicity through the TRAIL-DR5 axis

Abstract Adoptive T cell therapy (ACT) has shown promising therapeutic outcomes in patients with hematological malignancies. However, the success of ACT is limited to a small fraction of treated patients. Hence, developing new strategies to enhance the potency of ACT are urgently needed for better therapeutic outcomes. Our previous study demonstrated that inducing oxidative stress in tumor cells is critically involved in tumor rejection by ACT. In the current study, we report that indomethacin, a prototypical non-steroidal anti-inflammatory drug (NSAID), can intensify ROS in tumor cells and sensitize them to ACT. Mechanistically, our data indicate that indomethacin treatment leads to enhanced expression of death receptor 5 (DR5) in tumor cells, rendering them more susceptible to TNF-related apoptosis-inducing ligand (TRAIL)-induced cell death. We found that tumor-specific T cells upregulated TRAIL expression upon adoptive transfer. Using genetic-based approaches, we showed that DR5-deficient tumor cells were unresponsive to the beneficial effect of indomethacin, while overexpressing TRAIL in donor T cells led to further improvement in mouse survival. Collectively, our study demonstrates that the pro-oxidative feature of selected NSAIDs can be exploited to augment the efficacy of T cell therapy. Our findings provide a strong rationale for targeting tumor redox to achieve more effective tumor destruction through the combination of pro-oxidants and ACT.

Hepatic thermal injury promotes colorectal cancer engraftment in C57/black 6 mice.

Treatment options for liver metastases (primarily colorectal cancer) are limited by high recurrence rates and persistent tumor progression. Surgical approaches to management of these metastases typically use heat energy including electrocautery, argon beam coagulation, thermal ablation of surgical margins for hemostasis, and preemptive thermal ablation to prevent bleeding or to effect tumor destruction. Based on high rates of local recurrence, these studies assess whether local effects of hepatic thermal injury (HTI) might contribute to poor outcomes by promoting a hepatic microenvironment favorable for tumor engraftment or progression due to induction of procancer cytokines and deleterious immune infiltrates at the site of thermal injury. To test this hypothesis, an immunocompetent mouse model was developed wherein HTI was combined with concomitant intrasplenic injection of cells from a well-characterized MC38 colon carcinoma cell line. In this model, HTI resulted in a significant increase in engraftment and progression of MC38 tumors at the site of thermal injury. Furthermore, there were local increases in expression of messenger ribonucleic acid (mRNA) for hypoxia-inducible factor-1α (HIF1α), arginase-1, and vascular endothelial growth factor α and activation changes in recruited macrophages at the HTI site but not in untreated liver tissue. Inhibition of HIF1α following HTI significantly reduced discreet hepatic tumor development (P = 0.03). Taken together, these findings demonstrate that HTI creates a favorable local environment that is associated with protumorigenic activation of macrophages and implantation of circulating tumors. Discrete targeting of HIF1α signaling or inhibiting macrophages offers potential strategies for improving the outcome of surgical management of hepatic metastases where HTI is used.

Durable anticancer immunity from intratumoral administration of IL-23, IL-36γ, and OX40L mRNAs.

Many solid cancers contain dysfunctional immune microenvironments. Immune system modulators that initiate responses to foreign pathogens could be promising candidates for reigniting productive responses toward tumors. Interleukin-1 (IL-1) and IL-12 cytokine family members cooperate at barrier tissues after microbial invasion, in human inflammatory diseases, and in antitumoral immunity. IL-36γ, in classic alarmin fashion, acts in damaged tissues, whereas IL-23 centrally coordinates immune responses to danger signals. In this study, direct intratumoral delivery of messenger RNAs (mRNAs) encoding these cytokines produced robust anticancer responses in a broad range of tumor microenvironments. The addition of mRNA encoding the T cell costimulator OX40L increased complete response rates in treated and untreated distal tumors compared to the cytokine mRNAs alone. Mice exhibiting complete responses were subsequently protected from tumor rechallenge. Treatments with these mRNA mixtures induced downstream cytokine and chemokine expression, and also activated multiple dendritic cell (DC) and T cell types. Consistent with this, efficacy was dependent on Batf3-dependent cross-presenting DCs and cytotoxic CD8+ T cells. IL-23/IL-36γ/OX40L triplet mRNA mixture triggered substantial immune cell recruitment into tumors, enabling effective tumor destruction irrespective of previous tumoral immune infiltrates. Last, combining triplet mRNA with checkpoint blockade led to efficacy in models otherwise resistant to systemic immune checkpoint inhibition. Human cell studies showed similar cytokine responses to the individual components of this mRNA mixture, suggesting translatability of immunomodulatory activity to human patients.

A perylene diimide zwitterionic polymer for photoacoustic imaging guided photothermal/photodynamic synergistic therapy with single near-infrared irradiation.

Phototherapy has great promise for precise cancer diagnosis and effective therapy, but the development of one multifunctional nanoplatform for synergistic photodynamic therapy (PDT) and photothermal therapy (PTT) at a single excitation wavelength remains a challenge. In this work, a perylene diimide zwitterionic polymer PDS-PDI was synthesized via atom transfer radical polymerization (ATRP). This polymer was designed for photoacoustic imaging (PAI) guided synergistic PDT and PTT with single 660 nm near-infrared (NIR) light irradiation. The prepared PDS-PDI polymer presents high photothermal conversion efficiency (η≈ 40%) and efficient singlet oxygen quantum yield (ΦΔ≈ 16.7%) under 660 nm laser irradiation. Polymer PDS-PDI also acts as a contrast agent for PAI, offering real-time monitoring in tumor sites. Additionally, in vitro and in vivo assays indicate that polymer PDS-PDI has good biocompatibility and effective tumor destruction ability under 660 nm laser irradiation. In brief, polymer PDS-PDI prepared in this study could be applied as a dual-mode phototherapeutic agent under single laser irradiation.

Bone targeting study of tetracycline grafted PLGA nanoparticles drug delivery system

as promoting the precision treatment of cancer and mitigating undesired side effects. We present a new precision cancer nanomedicine based on Bi2S3 nanorods (NRs) designed specifically for multispectral optoacoustic tomography (MSOT)/X-ray computed tomography (CT) guided photothermal therapy (PTT). Multimodality imaging provides PTT with real-time guidance to diagnose disease, guide procedures, monitor therapeutic response, and treat disease with greater specificity and sensitivity. The as-prepared Bi2S3 NRs possess ideal photothermal effect and contrast enhancement in MSOT/CT bimodal imaging. These features make them simultaneously act as ‘satellite’ and ‘precision targeted weapon’ for the visual guide to destruction of tumors in vivo, realizing effective tumor destruction and metastasis inhibition after intravenous injection. In addition, toxicity screening confirms that Bi2S3 NRs have well biocompatibility. This triple-modality-nanoparticle approach enables simultaneously precise cancer therapy and therapeutic monitoring.

Clinical deployment of antibodies for treatment of melanoma.

The concept of using immunotherapy to treat melanoma has existed for decades. The rationale comes from the knowledge that many patients with melanoma have endogenous immune responses against their tumor cells and clinically meaningful tumor regression can be achieved in a minority of patients using cytokines such as interleukin-2 and adoptive cellular therapy. In the last 5 years there has been a revolution in the clinical management of melanoma in large measure based on the development of antibodies that influence T cell regulatory pathways by overcoming checkpoint inhibition and providing co-stimulation, either of which results in significantly more effective immune-mediated tumor destruction. This review will describe the pre-clinical and clinical application of antagonistic antibodies targeting the T-cell checkpoints cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death 1 (PD-1), and agonistic antibodies targeting the costimulatory pathways OX40 and 4-1BB. Recent progress and opportunities for future investigation of combination antibody therapy will be described.

Bismuth sulfide nanorods as a precision nanomedicine for in vivo multimodal imaging-guided photothermal therapy of tumor.

Here, we present a precision cancer nanomedicine based on Bi(2)S(3) nanorods (NRs) designed specifically for multispectral optoacoustic tomography (MSOT)/X-ray computed tomography (CT)-guided photothermal therapy (PTT). The as-prepared Bi(2)S(3) NRs possess ideal photothermal effect and contrast enhancement in MSOT/CT bimodal imaging. These features make them simultaneously act as "satellite" and "precision targeted weapon" for the visual guide to destruction of tumors in vivo, realizing effective tumor destruction and metastasis inhibition after intravenous injection. In addition, toxicity screening confirms that Bi(2)S(3) NRs have well biocompatibility. This triple-modality-nanoparticle approach enables simultaneously precise cancer therapy and therapeutic monitoring.

Influence of electrode array parameters used in electrotherapy on tumor growth kinetics: A mathematical simulation

Evaluation of the distance between the electrodes, voltage applied to them, and number of electrodes in tumor growth kinetics is very useful for effective tumor destruction when electrotherapy is used. However, a study of this type has not yet been proposed. The aim of this paper is to simulate the influence of such parameters and the point–point electrode configuration on the tumor growth kinetics through a Modified Gompertz Equation. The results show a good agreement between the simulations performed in this study and the experimental results reported by our group and other authors. A critical distance between electrodes and a threshold ratio between the applied electric field and that distributed in the tumor are revealed, for which higher electrotherapy antitumor effectiveness is reached. In conclusion, electrotherapy antitumor effectiveness not only depends on the distance between the electrodes, voltage applied to them, and number of electrodes, but also on the ratio between the applied electric field and that distributed in the tumor. In addition, the results of these simulations may be used to help physicians choose the most appropriate treatment for patients with malignant solid tumors, as we have implemented in a current clinical trial.

Hepatocellular carcinoma: new options for image‐guided ablation

Image-guided percutaneous ablation is currently accepted as the best therapeutic choice for patients with early-stage hepatocellular carcinoma (HCC) when transplantation and resection are precluded. Several methods for chemical or thermal tumor destruction have been developed and tested clinically during the past two decades. The seminal technique used for local treatment of HCC has been percutaneous ethanol injection (PEI). Several studies have provided indirect evidence that PEI improves the natural history of nonsurgical patients with early-stage HCC. Its major limitation is the high rate of local recurrence. Radiofrequency (RF) ablation has been the most widely assessed alternative to PEI. Five randomized controlled trials have shown that RF ablation achieves more effective and reproducible tumor destruction than PEI, leading to a better local control of the disease. As a result, RF ablation has been established as the primary ablative modality. The value of newer thermal and non-thermal methods for local tumor treatment, such as microwave ablation, irreversible electroporation (IRE), and light activated drug therapy, should be investigated in the setting of randomized controlled trials.

Distributions of the potential and electric field of an electrode elliptic array used in tumor electrotherapy: Analytical and numerical solutions

To estimate the potential and electric field generated by any electrode array is very useful in effective tumor destruction. At present, an electrode array that takes into account the ellipsoidal geometry of the solid tumors has not been proposed. We present both analytical and numerical solutions for the potential and electric field in a solid tumor established by an electrode array with elliptic shape which may be used in vitro, in vivo and in clinical studies for cancer treatment with electrotherapy. These analytical and numerical solutions are obtained using multipole expansion and the finite difference method. Distributions of potential and electric field magnitudes are computed in function of the eccentricity of an elliptical array and compared with those obtained with a circular array of electrode. Maximum difference and Root Means Square Error are used to compare the distributions of the potential and electric field in leading-order and first-order correction and between the analytical and numerical solutions. The results show a good agreement between these distributions in both orders and the analytical and numerical solutions. It was concluded that the mathematical approach presented in this study is a tool for a rapid design of electrode elliptical arrays in order to induce the maximum destruction of the tumor. Moreover, it is shown that, for all values of eccentricity, there is a good correspondence between the distributions of the potential and the electric field for leading-order and first-order correction and for both the analytical and numerical solutions.

Concerted Potent Humoral Immune Responses to Autoantigens Are Associated with Tumor Destruction and Favorable Clinical Outcomes without Autoimmunity

The therapeutic importance of immune responses against single versus multiple antigens is poorly understood. There also remains insufficient understanding whether responses to one subset of antigens are more significant than another. Autoantibodies are frequent in cancer patients. They can pose no biological significance or lead to debilitating paraneoplastic syndromes. Autoreactivity has been associated with clinical benefits, but the magnitude necessary for meaningful results is unknown. Autologous tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor generate immune infiltrates in preexisting metastases with associated tumor destruction. We sought to identify targets of responses from this vaccination strategy. Postvaccination sera used in screening a cDNA expression library prepared from a densely infiltrated metastasis of a long-term surviving melanoma patient identified several autoantigens. Additional autoantigens were identified through similar screenings in non-small cell lung cancer and murine models, and proteins implicated in cancer propagation. ELISAs for several targets were established using recombinant proteins, whereas others were evaluated by petit serologies. Eleven gene products were identified through serologic screening from two patients showing highly favorable clinical outcomes. A subset of antigens revealed significant changes in antibody titers compared with weak responses to other proteins. Time course analyses showed coordinated enhanced titers against several targets as a function of vaccination in responding patients. This study shows the range of biologically significant antigens resulting from a whole-cell vaccine. Targets include autoantigens that are components of cell cycle regulation. Potent antibody responses against multiple autoantigens are associated with effective tumor destruction without clinical autoimmunity.

Light delivery over extended time periods enhances the effectiveness of photodynamic therapy.

The rate of energy delivery is a principal factor determining the biological consequences of photodynamic therapy (PDT). In contrast to conventional high-irradiance treatments, recent preclinical and clinical studies have focused on low-irradiance schemes. The objective of this study was to investigate the relationship between irradiance, photosensitizer dose, and PDT dose with regard to treatment outcome and tumor oxygenation in a rat tumor model. Using the photosensitizer HPPH (2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide), a wide range of PDT doses that included clinically relevant photosensitizer concentrations was evaluated. Magnetic resonance imaging and oxygen tension measurements were done along with the Evans blue exclusion assay to assess vascular response, oxygenation status, and tumor necrosis. In contrast to high-incident laser power (150 mW), low-power regimens (7 mW) yielded effective tumor destruction. This was largely independent of PDT dose (drug-light product), with up to 30-fold differences in photosensitizer dose and 15-fold differences in drug-light product. For all drug-light products, the duration of light treatment positively influenced tumor response. Regimens using treatment times of 120 to 240 min showed marked reduction in signal intensity in T2-weighted magnetic resonance images at both low (0.1 mg/kg) and high (3 mg/kg) drug doses compared with short-duration (6-11 min) regimens. Significantly greater reductions in pO(2) were observed with extended exposures, which persisted after completion of treatment. These results confirm the benefit of prolonged light exposure, identify vascular response as a major contributor, and suggest that duration of light treatment (time) may be an important new treatment variable.

Heat shock protein expression and injury optimization for laser therapy design

Hyperthermia can induce heat shock protein (HSP) expression in tumor regions where non-lethal temperature elevation occurs, enhancing cell viability and resistance to chemotherapy and radiation treatments typically employed in conjunction with thermal therapy. However, HSP expression control has not been incorporated into current thermal therapy design. Treatment planning models based on achieving the desired post-therapy HSP expression and injury distribution in the tumor and healthy surrounding tissue can enable design of more effective thermal therapies that maximize tumor destruction and minimize healthy tissue injury. An optimization algorithm for prostate cancer laser therapy design was integrated into a previously developed treatment planning model, permitting prediction and optimization of the spatial and temporal temperature, HSP expression, and injury distributions in the prostate. This optimization method is based on dosimetry guidelines developed from measured HSP expression kinetics and injury data for normal and cancerous prostate cells and tumors exposed to hyperthermia. The optimization model determines laser parameters (wavelength, power, pulse duration, fiber position, and number of fibers) necessary to satisfy prescribed HSP expression and injury distributions in tumor and healthy tissue. Optimization based on achieving desired injury and HSP expression distributions within the tumor and normal tissue permits more effective tumor destruction and diminished injury to healthy tissue compared to temperature driven optimization strategies. Utilization of the treatment planning optimization model can permit more effective tumor destruction by mitigating tumor recurrence and resistance to chemotherapy and radiation arising from HSP expression and insufficient injury.