Salivary CD44 and Total Protein Levels to Detect Risk for Oral and Oropharyngeal Cancer Recurrence: A Nonrandomized Clinical Trial.

Importance: Oral and oropharyngeal cancer have low survival rates, and incidence continues to increase. Objective: To determine whether soluble CD44 and total protein (TP) are useful for monitoring head and neck cancer recurrence, either used in a point-of-care (POC) test or as individual laboratory-based biomarkers. Design, Setting, and Participants: This multi-institutional nonrandomized clinical trial testing a novel diagnostic/screening assay took place across the University of California, San Diego; Johns Hopkins University; the Greater Baltimore Medical Center; New York University; and the San Diego Veterans Affairs Hospital. Patients with newly biopsy-proven, untreated oral cavity and oropharyngeal cancer were enrolled. Patients were enrolled April 2017 to April 2019, and data were analyzed December 2022 to June 2023. Exposure: POC salivary oral rinse test. Main Outcomes and Measures: Oral rinses were collected at pretreatment baseline and 3, 6, 12, and 18 months after completion of therapy; participants were then followed up for 3 years to define disease status. Associations of baseline characteristics with a positive test were evaluated by Fisher exact test. The association of a positive value on the CD44 or TP test with progression-free survival was evaluated in an adjusted multivariable proportional hazards model. Results: Of 172 patients enrolled, the mean (SD) age was 62.5 (10.2) years, and 122 (70.9%) identified as male. Additionally, 92 patients (53.3%) had never smoked, 99 (57.6%) formerly or currently drank alcohol, and 113 (65.7%) presented with oropharyngeal cancers, which were positive for human papillomavirus in 95 (84.1%). Tumor site was associated with test results at baseline; patients with oral cavity cancer had a higher baseline positive POC test rate (47 of 51 [92.2%]) compared to patients with oropharyngeal cancer (85 of 110 [77.3%]). Using Cox regression models with CD44 or TP level as a time-varying covariate, a higher CD44 level showed a statistically significant association with a higher hazard of recurrence (hazard ratio, 1.06; 95% CI, 1.00-1.12), though the TP level was not statistically significant. In multivariate adjusted analysis, higher CD44 and TP levels were associated with increased hazard ratios of recurrence of 1.13 (95% CI, 1.04-1.22) and 3.51 (95% CI, 1.24-9.98), respectively. Conclusion and Relevance: In this multi-institutional nonrandomized clinical trial of an assay, posttreatment longitudinal monitoring for elevated salivary CD44 and TP levels using an enzyme-linked immunosorbent assay-based laboratory test identified patients at increased risk of future cancer recurrence. The CD44 and TP rapid POC test holds some promise, but further development is needed for this indication. Trial Registration: ClinicalTrials.gov Identifier: NCT03148665.

Enzyme-free and rapid colorimetric analysis of osteopontin via triple-helix aptamer probe coupled with catalytic hairpin assembly reaction.

BACKGROUND: Osteopontin (OPN) is closely associated with tumorigenesis, growth, invasion, and immune escape and it serves as a plasma biomarker for hepatocellular carcinoma (HCC). Nevertheless, the accurate and rapid detection of low-abundance OPN still poses significant challenges. Currently, the majority of protein detection methods rely heavily on large precision instruments or involve complex procedures. Therefore, developing a simple, enzyme-free, rapid colorimetric analysis method with high sensitivity is imperative. RESULTS: In this study, we have developed a portable colorimetric biosensor by integrating the triple-helix aptamer probe (THAP) and catalytic hairpin assembly (CHA) strategy, named as T-CHA. After binding to the OPN, the trigger probe can be released from THAP, then initiates the CHA reaction and outputs the signal through the formation of a G-quadruplex/Hemin DNAzyme with horseradish peroxidase-like activity. Consequently, this colorimetric sensor achieves visual free-labeled detection without additional fluorophore modification and allows for accurate quantification by measuring the optical density of the solution at 650 nm. Under optimal conditions, the logarithmic values of various OPN concentrations exhibit satisfactory linearity in the range of 5 pg mL-1 to 5 ng mL-1, with a detection limit of 2.04 pg mL-1. Compared with the widely used ELISA strategy, the proposed T-CHA strategy is rapid (∼105 min), highly sensitive, and cost-effective. SIGNIFICANCE: The T-CHA strategy, leveraging the low background leakage of THAP and the high catalytic efficiency of CHA, has been successfully applied to the detection of OPN in plasma, demonstrating significant promise for the early diagnosis of HCC in point-of-care testing. Given the programmability of DNA and the universality of T-CHA, it can be readily modified for analyzing other useful tumor biomarkers.

Impact of Treatment Response on Risk of Serious Infections in Patients With Crohn's Disease: Secondary Analysis of the PYRAMID Registry.

BACKGROUND & AIMS: Traditional risk factors for serious infections with advanced therapies in patients with Crohn's disease (CD) have been assessed at baseline before starting therapy. We evaluated the impact of treatment response on the risk of serious infections in adalimumab-treated patients with CD through secondary analysis of the PYRAMID registry (NCT00524537). METHODS: We included patients with CD who initiated adalimumab and classified them as treatment responders (achieved steroid-free clinical remission based on patient-reported outcomes) vs nonresponders (not in steroid-free clinical remission) at 6 months after treatment initiation (landmark). We compared the risk of serious infections between responders vs nonresponders between 6 and 36 months after treatment initiation through stabilized inverse probability of treatment weighting Cox proportional hazards model. RESULTS: Of 1515 adalimumab-treated patients, 763 (50.4%) were classified as responders at 6 months (37 ± 13 y; 56% female; disease duration, 9.5 ± 8.5 y). Compared with nonresponders, responders were less likely to have moderate to severe symptoms (55.6% vs 33%), or require steroids (45.5% vs 17.3%) or opiates (6.6% vs 1.3%) at baseline, without any differences in disease location, perianal disease, and prior CD complications. During follow-up evaluation, using stabilized inverse probability of treatment weighting, responders were 34% less likely to experience serious infections compared with nonresponders (hazard ratio, 0.66; 95% CI, 0.46-0.96). Risk of gastrointestinal and extraintestinal infections was lower in responders vs nonresponders. CONCLUSIONS: Patients with CD who respond to adalimumab have a lower risk of developing serious infections compared with nonresponders. These findings underscore that initiation of advanced therapy for CD may lower the risk of serious infections through effective disease control and avoidance of corticosteroids.

Ultrasound-enhanced nano catalyst with ferroptosis-apoptosis combined anticancer strategy for metastatic uveal melanoma.

Uveal melanoma is the most common primary ocular tumor owing to its highly invasive and metastatic characteristics. Currently, standard clinical treatment has an unsatisfied curative effect due to the lack of an effective approach to inhibit the tumor metastasis. Therefore, it is necessary to develop a new strategy that can both restraint local tumors and suppress the ocular tumor metastasis. Herein, we developed ultrasound-responsive nanoparticles (FeP NPs) that can both hinder the growth of in situ ocular tumor and prevent the tumor metastasis through the ferroptosis-apoptosis combined-anticancer strategy. The FeP NPs were assembling by stimulating gallic acid-Fe (III) and paclitaxel, then could be internalized into tumor cells under the cooperative effect of ultrasound, which further activates the intracellular Fenton reaction and generates high reactive oxygen species levels, ultimately leading to mitochondrial damage, lipid per-oxidation, and apoptosis. The FeP NPs can efficiently inhibit the tumor growth in an orthotopic uveal melanoma model. More importantly, the level of the promoting-metastatic factor nerve growth factor receptor (NGFR) secreted by cancer cells is significantly reduced, further limits cancer metastasis to the cervical lymph node and finally inhibits lung metastasis of uveal melanoma. We believe that these designed ultrasound-enhanced nanoparticles possess potential clinical application for preventing the regeneration and metastasis of uveal melanoma.

S100A family is a group of immune markers associated with poor prognosis and immune cell infiltration in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common human cancers with poor prognosis in the world. HCC has become the second leading cause of cancer-related death in China. It is urgent to identify novel biomarker and valid target to effectively diagnose, treat or predict the prognosis of HCC. It has been reported that S100A family is closely related to cell proliferation and migration of different cancers. However, the values of S100As in HCC remain to be further analyzed. METHODS: We investigated the transcriptional and translational expression of S100As, as well as the value of this family in HCC patients from the various databases. RESULTS: S100A10 was most relevant to HCC. CONCLUSIONS: The results from HCC patients' tissues and different cells also confirmed the role of S100A10 in HCC. Furthermore, we proved that S100A10 could influenced the cell proliferation of HCC cells via ANXA2/Akt/mTOR pathway. However, it would appear that the relationship between S100A10 and HCC is complex and requires more research.

Opportunities and challenges of natural killer cell-derived extracellular vesicles.

Extracellular vesicles (EVs) are increasingly recognized as important intermediaries of intercellular communication. They have significant roles in many physiological and pathological processes and show great promise as novel biomarkers of disease, therapeutic agents, and drug delivery tools. Existing studies have shown that natural killer cell-derived EVs (NEVs) can directly kill tumor cells and participate in the crosstalk of immune cells in the tumor microenvironment. NEVs own identical cytotoxic proteins, cytotoxic receptors, and cytokines as NK cells, which is the biological basis for their application in antitumor therapy. The nanoscale size and natural targeting property of NEVs enable precisely killing tumor cells. Moreover, endowing NEVs with a variety of fascinating capabilities via common engineering strategies has become a crucial direction for future research. Thus, here we provide a brief overview of the characteristics and physiological functions of the various types of NEVs, focusing on their production, isolation, functional characterization, and engineering strategies for their promising application as a cell-free modality for tumor immunotherapy.

Vascular endothelial growth factor A is a potential prognostic biomarker and correlates with immune cell infiltration in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths among cancer patients. Vascular endothelial growth factor A (VEGFA) is involved in regulating biological processes, such as angiogenesis and vascular permeability, and is very closely related to the pathogenesis of various tumours, especially vascular-rich, solid tumours. Clinical data of patients with HCC and other tumours were analysed through public databases, such as the TCGA database, Gene Expression Omnibus database, Human Protein Atlas database, STRING, Tumour Immune Estimation Resource and Kaplan-Meier Plotter. The tumour tissues and adjacent normal tissues of patients with HCC from Hunan Provincial People's Hospital were collected to verify the expression of VEGFA by immunohistochemistry, immunofluorescence, Western blotting and qPCR. VEGFA expression is elevated in multiple tumour types and correlates with the prognosis of tumour patients. VEGFA is involved in regulating the tumour microenvironment and immune cell function in tumour development. Inhibition of VEGFA reduces proliferation, invasion, and migration and promotes apoptosis in HCC cells. VEGFA is a potential predictive biomarker for the diagnosis and prognosis of HCC.

Quercetin Inhibits Intrahepatic Cholangiocarcinoma by Inducing Ferroptosis and Inhibiting Invasion via the NF-[Formula: see text]B Pathway.

Intrahepatic cholangiocarcinoma (ICC) is a rare, highly fatal hepatobiliary malignancy, with very limited treatment options and, consequently, a poor prognosis. Recently, emerging evidence has suggested the potential of quercetin (QE) for use in cancer therapy. The purpose of this study is to investigate whether QE could inhibit ICC. The effects of QE on the proliferation, apoptosis, and invasion of ICC were analyzed in vitro. The inhibitory effect of QE on ICC was also verified in vivo. The RNA sequence was applied to explore the mechanism of QE. Functional verification was also performed after RNA sequencing using activators and inhibitors of nuclear factor-kappa-B (NF-[Formula: see text]B) and ferroptosis. The results showed that QE could inhibit the proliferation and survival of ICC cells, induce the arrest of ICC cells in the G1 phase, promote the apoptosis of ICC cells, and inhibit the invasion of ICC cells. Furthermore, QE could promote ferroptosis in ICC cells by inhibiting the NF-[Formula: see text]B pathway. In conclusion, QE is a new ferroptosis inducer and NF-[Formula: see text]B inhibitor that can not only induce ferroptosis, but also inhibit the invasion of ICC cells, providing a prospective strategy for the treatment of ICC.

Corrigendum: The incidence risk of breast and gynecological cancer by antidepressant use: A systematic review and dose-response meta-analysis of epidemiological studies involving 160,727 patients.

[This corrects the article DOI: 10.3389/fonc.2022.939636.].

Protein-free, ultrasensitive miRNA analysis based on an entropy-driven catalytic reaction switched on a smart-responsive DNAzyme dual-walker amplification strategy.

MicroRNAs (miRNAs), useful biomarkers for cancer diagnosis, play an important role in tumorigenesis and progression, but many of the current analysis methods can suffer from excessive protease dependence, being time-consuming and unsatisfactory performance. Therefore, a reliable sensing strategy for the protein-free, ultrasensitive analysis of tumor-associated miRNAs is desired. The proposed dual-walker biosensing strategy based on an entropy-driven catalytic (EDC) walker coupled with a smart-responsive DNAzyme walker was demonstrated for the dual-amplification detection of miRNA-21. Namely, the target miRNA-21 initiates the three-stranded substrate complex of the traditional EDC circuit to release the input trigger of the Dz walker, which recognizes the circular binding domain to restore the cleavage activity of the DzS-AuNP walker. The fluorescence signal continuously released from the AuNPs was recorded by a fluorescence reader for miRNA-21 sensing. The optimized dual-walker exhibited appreciable sensitivity with a detection limit of 70 fM, satisfactory flexibility, fine specificity and ideal stability for clinical serum sample assays. The proposed strategy may open a new avenue for the development of powerful DNA molecular tools for cancer diagnosis.

The incidence risk of breast and gynecological cancer by antidepressant use: A systematic review and dose-response meta-analysis of epidemiological studies involving 160,727 patients.

Background and objective: Antidepressants are widely prescribed to treat depression and anxiety disorders that may become chronic conditions among women. Epidemiological studies have yielded inconsistent results on the correlation between antidepressant use and the incidence risk of female breast and gynecological cancer, along with uncertain dose-response relationship. Therefore, we performed a systematic review and dose-response meta-analysis to investigate the association. Methods: Web of Science, Embase, PubMed, The Cochrane Library, and PsycINFO were systematically searched in January 2022, with no language limits. Random-effect models were used to calculate pooled effect sizes and 95% confidence intervals between studies. Linear and non-linear dose-response analyses were performed to evaluate the dose or duration of antidepressant use affecting the incidence risk of female breast and gynecological cancer. Further subgroup analyses were systematically performed by stratifying almost all study characteristics and important potential confounders, in order to further clarify and validate the important potential hypotheses regarding the biological mechanism underlying this association. Results: Based on a systematic literature search, 34 eligible studies (27 case-control studies and 7 cohort studies) involving 160,727 female breast and gynecological cancer patients found that antidepressant use did not increase the incidence risk of female breast and gynecological cancer (pooled OR: 1.01; 95% CI: 0.97, 1.04, I² = 71.5%, p < 0.001), and even decreased the incidence risk of ovarian cancer (pooled OR: 0.91; 95% CI: 0.83, 1, I² = 17.4%, p = 0.293). There were a non-linear dose-response relationship (p non-linearity < 0.05) between the duration of antidepressant use and incidence risk of female breast cancer, and an inverse linear dose-response relationship between antidepressant use and the incidence risk of gynecological cancer, specifically with an increase of cumulative defined daily dose or duration to a high level, like 25,550 doses (OR: 0.91, 95% CI: 0.85-0.98, p linearity < 0.05) or 4,380 days (OR: 0.82; 95% CI: 0.7, 0.96, p linearity < 0.05), compared to never antidepressant users. Conclusion: This systematic review and dose-response meta-analysis found that antidepressant use did not increase the incidence risk of female breast and gynecological cancer and even decreased the incidence risk of ovarian cancer, along with a non-linear or linear dose-response relationship. Systematic Review Registration: PROSPERO https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=313364, identifier CRD42022313364.

A phase I study of avelumab, palbociclib, and cetuximab in patients with recurrent or metastatic head and neck squamous cell carcinoma.

OBJECTIVES: We aimed to test the safety of the CDK4/6 inhibitor palbociclib in combination with the EGFR inhibitor cetuximab and the PD-L1 inhibitor avelumab in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). MATERIALS AND METHODS: This phase I study enrolled eligible adult patients with R/M HNSCC into three sequential single dose-escalation cohorts of palbociclib (75, 100, and 125 mg) PO daily on days 1 to 21 of a 28-day cycle in combination with avelumab 10 mg/kg IV every 2 weeks and cetuximab 400 mg/m2IV on day 1, then 250 mg/m2weekly thereafter. The study followed a 3 + 3 design with no intra-patient escalation. The primary objective was to identify the recommended phase II dose (RP2D); secondary objectives included overall response rate (ORR), duration of response (DOR), progression free survival (PFS), and overall survival (OS). RESULTS: Palbociclib in combination with avelumab and cetuximab was well tolerated, with rash and fatigue being the most common adverse events. A single dose-limiting toxicity was observed at the 125 mg dose of palbociclib: a grade 3 infusion reaction related to cetuximab. The RP2D of palbociclib is 125 mg, with avelumab and cetuximab at standard doses. The ORR by RECIST v1.1 was 42 %, the median DOR and OS have not been reached. Median PFS was 6.5 months. CONCLUSIONS: The combination of avelumab, cetuximab, and palbociclib was well tolerated and supports further evaluation in patients with R/M HNSCC. CLINICAL TRIAL REGISTRATION NUMBER: NCT03498378.

Iodine-125 seed implantation combined chemotherapy for metastatic pancreatic adenocarcinoma with primary colon cancer: A case report.

RATIONALE: Colon cancer has a distinct migration aptitude. However, pancreatic metastasis is rare and treatment of inoperable pancreatic cancers is seldom seen. PATIENT CONCERNS: A 47-year-old woman presented 2-month history of abdominal pain and abdominal distention, with anal cessation of exhaust and defecation for 4 days. A colon cancer radical resection was performed when she diagnosed with colon cancer. After 26 months, the patient complained shoulder and back pain. Multiple intraperitoneal metastases and nonisolated pancreatic metastasis of colon cancer were diagnosed. DIAGNOSIS: Metastatic pancreatic adenocarcinoma (MPA) with primary colon cancer. INTERVENTION: Iodine-125 seed implantation combined chemotherapy. OUTCOMES: She remains free of cancer metastasis and recurrence, and has a good quality of life during the period. LESSONS SUBSECTIONS: Iodine-125 seed implantation is an effective and safe strategy for unresectable metastatic pancreatic cancer. Iodine-125 seed implantation combined with chemotherapy improve survival for advanced pancreatic metastasis of colon cancer.

Microalgae-based oral microcarriers for gut microbiota homeostasis and intestinal protection in cancer radiotherapy.

Protecting the whole small intestine from radiation-induced intestinal injury during the radiotherapy of abdominal or pelvic solid tumors remains an unmet clinical need. Amifostine is a promising selective radioprotector for normal tissues. However, its oral application in intestinal radioprotection remains challenging. Herein, we use microalga Spirulina platensis as a microcarrier of Amifostine to construct an oral delivery system. The system shows comprehensive drug accumulation and effective radioprotection in the whole small intestine that is significantly superior to free drug and its enteric capsule, preventing the radiation-induced intestine injury and prolonging the survival without influencing the tumor regression. It also shows benefits on the gut microbiota homeostasis and long-term safety. Based on a readily available natural microcarrier, this work presents a convenient oral delivery system to achieve effective radioprotection for the whole small intestine, providing a competitive strategy with great clinical translation potential.

Zinc oxide nanosphere for hydrogen sulfide scavenging and ferroptosis of colorectal cancer.

BACKGROUND: Colorectal cancer is a common malignancy occurring in the digestive system and ranks second in cancer mortality worldwide. In colorectal cancer, hydrogen sulfide (H2S) is selectively upregulated, resulting in the further exacerbation of the disease. Therefore, the clearance of H2S and the regulation of the enzymes on the H2S pathways are of great significance for colorectal cancer therapy. METHODS: Here, we investigated the H2S content in various clinical tumor tissues from patients and confirmed that overproduced concentration of H2S in colorectal cancer. Accordingly, we developed an H2S-responsive nanoplatform based on zinc oxide coated virus-like silica nanoparticles (VZnO) for the therapy of colorectal cancer. RESULTS: Owing to its excellent H2S scavenging ability, VZnO could effectively reduce H2S content in colorectal cancer to prohibit the growth of CT26 and HCT116 colorectal cancer cells. Moreover, the removal of H2S in colorectal cancer also leads to tumor inhibition through activating ferroptosis, a non-apoptotic form of cell death. The biosafety-related toxicological and pathological analysis confirmed the low toxicity and high safety of VZnO in colorectal cancer treatment. Furthermore, as an H2S-responsible nanosystem, VZnO appears to have no therapeutic effect on other non H2S rich cancers, such as the 4T1 breast cancer model. CONCLUSIONS: We anticipate that the H2S-depletion-induced ferroptosis strategy using zinc oxide-based nanomaterials would provide insights in designing nanomedicines for colorectal cancer-target theranostics and may offer clinical promise.

Aggregation-induced emission luminogens for image-guided surgery in non-human primates.

During the past two decades, aggregation-induced emission luminogens (AIEgens) have been intensively exploited for biological and biomedical applications. Although a series of investigations have been performed in non-primate animal models, there is few pilot studies in non-human primate animal models, strongly hindering the clinical translation of AIE luminogens (AIEgens). Herein, we present a systemic and multifaceted demonstration of an optical imaging-guided surgical operation via AIEgens from small animals (e.g., mice and rabbits) to rhesus macaque, the typical non-human primate animal model. Specifically, the folic conjugated-AIE luminogen (folic-AIEgen) generates strong and stable fluorescence for the detection and surgical excision of sentinel lymph nodes (SLNs). Moreover, with the superior tumor/normal tissue ratio and rapid tumor accumulation, folic-AIEgen successfully images and guides the precise resection of invisible cancerous metastases. Taken together, the presented strategies of folic-AIEgen based fluorescence intraoperative imaging and visualization-guided surgery show potential for clinical applications.

Low-dose X-ray enhanced tumor accumulation of theranostic nanoparticles for high-performance bimodal imaging-guided photothermal therapy.

BACKGROUND: Theranostic nanoparticles (NPs) have achieved rapid development owing to their capacity for personalized multimodal diagnostic imaging and antitumor therapy. However, the efficient delivery and bulk accumulation of NPs in tumors are still the decisive factors in improving therapeutic effect. It is urgent to seek other methods to alters tumor microenvironment (like vascular permeability and density) for enhancing the efficiency of nanoparticles delivery and accumulation at the tumor site. METHODS: Herein, we developed a Raman-tagged hollow gold nanoparticle (termed as HAuNP@DTTC) with surface-enhanced Raman scattering (SERS) property, which could be accumulated efficiently in tumor site with the pre-irradiation of low-dose (3 Gy) X-ray and then exerted highly antitumor effect in breast cancer model. RESULTS: The tumor growth inhibition (TGI) of HAuNP@DTTC-induced photothermal therapy (PTT) was increased from 60% for PTT only to 97%, and the lethal distant metastasis of 4T1 breast cancer (such as lung and liver) were effectively inhibited under the X-ray-assisted PTT treatment. Moreover, with the strong absorbance induced by localized surface plasmon resonance in near-infrared (NIR) region, the signals of Raman/photoacoustic (PA) imaging in tumor was also significantly enhanced after the administration of HAuNP@DTTC, indicating it could be used as the Raman/PA imaging and photothermal agent simultaneously under 808 nm laser irradiation. CONCLUSIONS: Our studied of the as-prepared HAuNP@DTTC integrated the Raman/PA imaging and PTT functions into the single platform, and showed the good prospects for clinical applications especially with the low-dose X-ray irradiation as an adjuvant, which will be a productive strategy for enhancing drug delivery and accumulation in tumor theranostics.

Calcium phosphate engineered photosynthetic microalgae to combat hypoxic-tumor by in-situ modulating hypoxia and cascade radio-phototherapy.

Rationale: Hypoxia is one of the crucial restrictions in cancer radiotherapy (RT), which leads to the hypoxia-associated radioresistance of tumor cells and may result in the sharp decline in therapeutic efficacy. Methods: Herein, living photosynthetic microalgae (Chlorella vulgaris, C. vulgaris), were used as oxygenators, for in situ oxygen generation to relieve tumor hypoxia. We engineered the surface of C. vulgaris (CV) cells with calcium phosphate (CaP) shell by biomineralization, to form a biomimetic system (CV@CaP) for efficient tumor delivery and in-situ active photosynthetic oxygenation reaction in tumor. Results: After intravenous injection into tumor-bearing mice, CV@CaP could remarkably alleviate tumor hypoxia by continuous oxygen generation, thereby achieving enhanced radiotherapeutic effect. Furthermore, a cascade phototherapy could be fulfilled by the chlorophyll released from photosynthetic microalgae combined thermal effects under 650 nm laser irradiation. The feasibility of CV@CaP-mediated combinational treatment was finally validated in an orthotropic breast cancer mouse model, revealing its prominent anti-tumor and anti-metastasis efficacy in hypoxic-tumor management. More importantly, the engineered photosynthetic microalgae exhibited excellent fluorescence and photoacoustic imaging properties, allowing the self-monitoring of tumor therapy and tumor microenvironment. Conclusions: Our studies of this photosynthetic microsystem open up a new dimension for solving the radioresistance issue of hypoxic tumors.