Advancements in Understanding and Preventing Obesity-Related Colon Cancer.

ABSTRACT: Obesity and colorectal cancer are global public health issues, with the prevalence of both conditions increasing over the last 4 decades. In the United States alone, the prevalence of obesity is greater than 40%, and this percentage is projected to increase past 50% by 2030. This review focuses on understanding the association between obesity and the risk of colorectal cancer while also highlighting hypotheses about molecular mechanisms underlying the link between these disease processes. We also consider whether those linkages can be disrupted via weight loss therapies, including lifestyle modifications, pharmacotherapy, bariatric surgery, and endobariatrics.

GSH-responsive polymeric micelles-based augmented photoimmunotherapy synergized with PD-1 blockade for eliciting robust antitumor immunity against colon tumor.

Phototherapy is a promising antitumor modality, which consists of photothermal therapy (PTT) and photodynamic therapy (PDT). However, the efficacy of phototherapy is dramatically hampered by local hypoxia in tumors, overexpression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand-1 (PD-L1) on tumor cells. To address these issues, self-assembled multifunctional polymeric micelles (RIMNA) were developed to co-deliver photosensitizer indocyanine green (ICG), oxygenator MnO2, IDO inhibitor NLG919, and toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). It is worth noting that RIMNA polymeric micelles had good stability, uniform morphology, superior biocompatibility, and intensified PTT/PDT effect. What's more, RIMNA-mediated IDO inhibition combined with programmed death receptor-1 (PD-1)/PD-L1 blockade considerably improved immunosuppression and promoted immune activation. RIMNA-based photoimmunotherapy synergized with PD-1 antibody could remarkably inhibit primary tumor proliferation, as well as stimulate the immunity to greatly suppress lung metastasis and distant tumor growth. This study offers an efficient method to reinforce the efficacy of phototherapy and alleviate immunosuppression, thereby bringing clinical benefits to cancer treatment.

Neoadjuvant envafolimab in a patient with MSI-H/dMMR colon cancer: a case report and literature review.

Clinical evidences of neoadjuvant immunotherapy in patients with mismatch repair deficient/microsatellite instability-high status (dMMR/MSI-H) colorectal cancer have not been well received. A 36-year-old man complained of recurrent right upper quadrant pain for more than 1 year, and the symptoms were not significantly relieved after 10 days of oral Changyanning tablet. The patient was finally diagnosed as dMMR/MSI-H colon cancer. Tumor regression was achieved after seven cycles of envafolimab treatment, and the patient obtained postoperative pathological complete response (pCR). Here, we report a case of MSI-H/dMMR transverse colon cancer, who obtained pCR after neoadjuvant envafolimab (a novel subcutaneous single-domain anti-PD-L1 antibody) with a favorable safety profile, aiming to enhance the experiences of comprehensive diagnosis and treatment of colon cancer.

Immune checkpoint inhibitors (ICIs) are a type of immunotherapy which can be used in the treatment of colorectal cancer. The authors here report the functions of envafolimab (a type of ICI) used before surgery to shrink tumor volume in colorectal cancer. A 36-year-old man suffered from repeated illness of right upper quadrant for over 1 year, and the illness were not recovered after 10 days of oral Changyanning tablet. The patient was finally diagnosed with colorectal cancer. After seven cycles of envafolimab treatment, tumor volume was significantly decreased, and the patient obtained favorable surgical outcomes with tolerable safety after surgery.

Hospital Accreditation Status and Treatment Differences Among Black Patients With Colon Cancer.

Importance: Hospital-level factors, such as hospital type or volume, have been demonstrated to play a role in treatment disparities for Black patients with cancer. However, data evaluating the association of hospital accreditation status with differences in treatment among Black patients with cancer are lacking. Objective: To evaluate the association of Commission on Cancer (CoC) hospital accreditation status with receipt of guideline-concordant care and mortality among non-Hispanic Black patients with colon cancer. Design, Setting, and Participants: This population-based cohort study used the National Program of Cancer Registries, which is a multicenter database with data from all 50 states and the District of Columbia, and covers 97% of the cancer population in the US. The participants included non-Hispanic Black patients aged 18 years or older diagnosed with colon cancer between January 1, 2018, and December 31, 2020. Race and ethnicity were abstracted from medical records as recorded by health care facilities and practitioners. The data were analyzed from December 7, 2023, to January 17, 2024. Exposure: CoC hospital accreditation. Main Outcome and Measures: Guideline-concordant care was defined as adequate lymphadenectomy during surgery for patients with stages I to III disease or chemotherapy administration for patients with stage III disease. Multivariable logistic regression models investigated associations with receipt of guideline-concordant care and Cox proportional hazards regression models assessed associations with 3-year cancer-specific mortality. Results: Of 17 249 non-Hispanic Black patients with colon cancer (mean [SD] age, 64.8 [12.8] years; 8724 females [50.6%]), 12 756 (74.0%; mean [SD] age, 64.7 [12.8] years) were treated at a CoC-accredited hospital and 4493 (26.0%; mean [SD] age, 65.1 [12.5] years) at a non-CoC-accredited hospital. Patients treated at CoC-accredited hospitals compared with those treated at non-CoC-accredited hospitals had higher odds of receiving guideline-concordant lymphadenectomy (adjusted odds ratio [AOR], 1.89; 95% CI, 1.69-2.11) and chemotherapy (AOR, 2.31; 95% CI, 1.97-2.72). Treatment at CoC-accredited hospitals was associated with lower cancer-specific mortality for patients with stages I to III disease who received surgery (adjusted hazard ratio [AHR], 0.87; 95% CI, 0.76-0.98) and for patients with stage III disease eligible for chemotherapy (AHR, 0.75; 95% CI, 0.59-0.96). Conclusions and Relevance: In this cohort study of non-Hispanic Black patients with colon cancer, patients treated at CoC-accredited hospitals compared with those treated at non-CoC-accredited hospitals were more likely to receive guideline-concordant care and have lower mortality risk. These findings suggest that increasing access to high-quality guideline-concordant care at CoC-accredited hospitals may reduce variations in cancer treatment and outcomes for underserved populations.

Engineered bacteria breach tumor physical barriers to enhance radio-immunotherapy.

Radiotherapy widely applied for local tumor therapy in clinic has been recently reinvigorated by the discovery that radiotherapy could activate systematic antitumor immune response. Nonetheless, the endogenous radio-immune effect is still incapable of radical tumor elimination due to the prevention of immune cell infiltration by the physical barrier in tumor microenvironment (TME). Herein, an engineered Salmonella secreting nattokinase (VNPNKase) is developed to synergistically modulate the physical and immune characteristics of TME to enhance radio-immunotherapy of colon tumors. The facultative anaerobic VNPNKase enriches at the tumor site after systemic administration, continuously secreting abundant NKase to degrade fibronectin, dredge the extracellular matrix (ECM), and inactivate cancer-associated fibroblasts (CAFs). The VNPNKase- dredged TME facilitates the infiltration of CD103+ dendritic cells (DCs) and thus the presentation of tumor-associated antigens (TAAs) after radiotherapy, recruiting sufficient CD8+ T lymphocytes to specifically eradicate localized tumors. Moreover, the pre-treatment of VNPNKase before radiotherapy amplifies the abscopal effect and achieves a long-term immune memory effect, preventing the metastasis and recurrence of tumors. Our research suggests that this strategy using engineered bacteria to breach tumor physical barrier for promoting immune cell infiltration possesses great promise as a translational strategy to enhance the effectiveness of radio-immunotherapy in treating solid tumors.

Is Hyperthermic Intraperitoneal Chemotherapy Appropriate for Colon Cancer?

Colorectal cancer (CRC) with peritoneal metastases is a complex disease and its management presents significant clinical challenges. In well-selected patients at experienced centers, CRS/hyperthermic intraperitoneal chemotherapy (HIPEC) can be performed with acceptable morbidity and is associated with prolonged survival. Based on the results of recent randomized controlled trials, HIPEC using oxaliplatin after CRS with shortened perfusion periods (30 minutes) is no longer recommended. There is a movement toward utilizing mitomycin C as a first-line intraperitoneal agent with extended perfusion times (90-120 minutes); however, there is currently little prospective evidence to support its widespread use.

Local therapy with combination TLR agonists stimulates systemic anti-tumor immunity and sensitizes tumors to immune checkpoint blockade.

Toll-like receptor (TLR) agonists are being developed as anti-cancer therapeutics due to their potent immunostimulatory properties. However, clinical trials testing TLR agonists as monotherapy have often failed to demonstrate significant improvement over standard of care. We hypothesized that the anti-cancer efficacy of TLR agonist immunotherapy could be improved by combinatorial approaches. To prevent increased toxicity, often seen with systemic combination therapies, we developed a hydrogel to deliver TLR agonist combinations at low doses, locally, during cancer debulking surgery. Using tumor models of WEHI 164 and bilateral M3-9-M sarcoma and CT26 colon carcinoma, we assessed the efficacy of pairwise combinations of poly(I:C), R848, and CpG in controlling local and distant tumor growth. We show that combination of the TLR3 agonist poly(I:C) and TLR7/8 agonist R848 drives anti-tumor immunity against local and distant tumors. In addition, combination of local poly(I:C) and R848 sensitized tumors to systemic immune checkpoint blockade, improving tumor control. Mechanistically, we demonstrate that local therapy with poly(I:C) and R848 recruits inflammatory monocytes to the tumor draining lymph nodes early in the anti-tumor response. Finally, we provide proof of concept for intraoperative delivery of poly(I:C) and R848 together via a surgically applicable biodegradable hydrogel.

Umbilical cord mesenchymal stem cells: A powerful fighter against colon cancer?

Colon cancer (CC) stands as one of the most common malignancies related to the gastrointestinal system, whose increasing incidence and death rates have been reported all over the world. Standard treatments for fighting cancers like CC comprise surgical approaches, chemotherapy, and radiotherapy, which are suggested by clinicians according to patients' conditions and disease stages. However, patients who utilize these modalities may suffer from serious side effects and adverse outcomes, for example, toxicity and tumor recurrence, as well as a low 5-year survival rate. The present shreds of evidence showed that mesenchymal stem cells (MSCs) can have a suitable capacity for treating different health problems, especially neoplasms. These multipotent stem cells can be isolated from several sources, such as the umbilical cord, bone marrow, adipose tissue, and placenta. Among these mesenchymal sources, umbilical cord-MSCs have gathered much attention in scientific societies due to their advantages (e.g., low immunogenicity, lack of ethical problems, and easy collection). These days, the efficacy of umbilical cord-MSCs and umbilical cord-MSCs-based strategies, such as conditioned medium, extracellular vesicles, and exosomes, on CC have been explored, and promising findings have been stated. Therefore, in this review, we aimed to summarize and debate evidence regarding the effects of UC-MSCs and their related products on CC with a focus on molecular and cellular mechanisms involved in its treatment and pathogenesis of this malignant tumor.

Neoadjuvant Chemotherapy in Colon Cancer: More Than Just an Optical Illusion.

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice.

MS-20 enhances the gut microbiota-associated antitumor effects of anti-PD1 antibody.

Cancer immunotherapy has been regarded as a promising strategy for cancer therapy by blocking immune checkpoints and evoking immunity to fight cancer, but its efficacy seems to be heterogeneous among patients. Manipulating the gut microbiota is a potential strategy for enhancing the efficacy of immunotherapy. Here, we report that MS-20, also known as "Symbiota®", a postbiotic that comprises abundant microbial metabolites generated from a soybean-based medium fermented with multiple strains of probiotics and yeast, inhibited colon and lung cancer growth in combination with an anti-programmed cell death 1 (PD1) antibody in xenograft mouse models. Mechanistically, MS-20 remodeled the immunological tumor microenvironment by increasing effector CD8+ T cells and downregulating PD1 expression, which were mediated by the gut microbiota. Fecal microbiota transplantation (FMT) from mice receiving MS-20 treatment to recipient mice increased CD8+ T-cell infiltration into the tumor microenvironment and significantly improved antitumor activity when combined with anti-PD1 therapy. Notably, the abundance of Ruminococcus bromii, which increased following MS-20 treatment, was positively associated with a reduced tumor burden and CD8+ T-cell infiltration in vivo. Furthermore, an ex vivo study revealed that MS-20 could alter the composition of the microbiota in cancer patients, resulting in distinct metabolic pathways associated with favorable responses to immunotherapy. Overall, MS-20 could act as a promising adjuvant agent for enhancing the efficacy of immune checkpoint-mediated antitumor therapy.

A combined radio-immunotherapy regimen eradicates late-stage tumors in mice.

Background: The majority of experimental approaches for cancer immunotherapy are tested against relatively small tumors in tumor-bearing mice, because in most cases advanced cancers are resistant to the treatments. In this study, we asked if even late-stage mouse tumors can be eradicated by a rationally designed combined radio-immunotherapy (CRI) regimen. Methods: CRI consisted of local radiotherapy, intratumoral IL-12, slow-release systemic IL-2 and anti- CTLA-4 antibody. Therapeutic effects of CRI against several weakly immunogenic and immunogenic mouse tumors including B78 melanoma, MC38 and CT26 colon carcinomas and 9464D neuroblastoma were evaluated. Immune cell depletion and flow cytometric analysis were performed to determine the mechanisms of the antitumor effects. Results: Tumors with volumes of 2,000 mm3 or larger were eradicated by CRI. Flow analyses of the tumors revealed reduction of T regulatory (Treg) cells and increase of CD8/Treg ratios following CRI. Rapid shrinkage of the treated tumors did not require T cells, whereas T cells were involved in the systemic effect against the distant tumors. Cured mice developed immunological memory. Conclusions: These findings underscore that rationally designed combination immunotherapy regimens can be effective even against large, late-stage tumors.

Establishing a model composed of immune-related gene-modules to predict tumor immunotherapy response.

At present, tumor immunotherapy has been widely applied to treat various cancers. However, the accuracy of predicting treatment efficacy has not yet achieved a significant breakthrough. This study aimed to construct a prediction model based on the modified WGCNA algorithm to precisely judge the anti-tumor immune response. First, we used a murine colon cancer model to screen corresponding DEGs according to different groups. GSEA was used to analyze the potential mechanisms of the immune-related DEGs (irDEGs) in each group. Subsequently, the intersection of the irDEGs in every group was acquired, and 7 gene-modules were mapped. Finally, 4 gene-modules including cogenes, antiPD-1 immu-genes, chemo immu-genes and comb immu-genes, were selected for subsequent study. Furthermore, a clinical dataset of gastric cancer patients receiving immunotherapy was enrolled, and the irDEGs were identified. A total of 34 vital irDEGs were obtained from the intersections of the vital irDEGs and the four gene-modules. Next, the vital irDEGs were analyzed by the modified WGCNA algorithm, and the correlation coefficients between the 4 gene-modules and the response status to immunotherapy were calculated. Thus, a prediction model based on correlation coefficients was built, and the corresponding model scores were acquired. The AUC calculated according to the model score was 0.727, which was non-inferior to that of the ESTIMATE score and the TIDE score. Meanwhile, the AUC calculated according to the classification of the model scores was 0.705, which was non-inferior to that of the ESTIMATE classification and the TIDE classification. The prediction accuracy of the model was validated in clinical datasets of other cancers.

Intratumoral injection of mRNA encoding survivin in combination with STAT3 inhibitor stattic enhances antitumor effects.

Intratumoral delivery of mRNA encoding immunostimulatory molecules can initiate a robust, global antitumor response with little side effects by enhancing local antigen presentation in the tumor and the tumor draining lymph node. Neoantigen-based mRNA nanovaccine can inhibit melanoma growth in mice by intratumoral injection. Myeloid-derived suppressor cells (MDSCs) suppress antitumor immune responses by secreting immunosuppressive agents, such as reactive oxygen species (ROS). Suppression of STAT3 activity by stattic may reduce MDSC-mediated immunosuppression in the TME and promote the antitumor immune responses. In this study, in vitro transcribed mRNA encoding tumor antigen survivin was prepared and injected intratumorally in BALB/c mice bearing subcutaneous colon cancer tumors. In vivo studies demonstrated that intratumoral survivin mRNA therapy could induce antitumor T cell response and inhibit tumor growth of colon cancer. Depletion of CD8+ T cells could significantly inhibit survivin mRNA-induced antitumor effects. RT-qPCR and ELISA analysis indicated that survivin mRNA treatment led to increased expression of receptor activator nuclear factor-κB ligand (RANKL). In vitro experiment showed that MDSCs could be induced from mouse bone marrow cells by RANKL and RANKL-induced MDSCs could produce high level of ROS. STAT3 inhibitor stattic suppressed activation of STAT3 and NF-κB signals, thereby inhibiting expansion of RANKL-induced MDSCs. Combination therapy of survivin mRNA and stattic could significantly enhance antitumor T cell response, improve long-term survival and reduce immunosuppressive tumor microenvironment compared to each monotherapy. In addition, combined therapy resulted in a significantly reduced level of tumor cell proliferation and an obviously increased level of tumor cell apoptosis in CT26 colon cancer-bearing mice, which could be conducive to inhibit the tumor growth and lead to immune responses to released tumor-associated antigens. These studies explored intratumoral mRNA therapy and mRNA-based combined therapy to treat colon cancer and provide a new idea for cancer therapy.

Colon Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology.

Colorectal cancer (CRC) is the fourth most frequently diagnosed cancer and the second leading cause of cancer death in the United States. Management of disseminated metastatic CRC involves various active drugs, either in combination or as single agents. The choice of therapy is based on consideration of the goals of therapy, the type and timing of prior therapy, the mutational profile of the tumor, and the differing toxicity profiles of the constituent drugs. This manuscript summarizes the data supporting the systemic therapy options recommended for metastatic CRC in the NCCN Guidelines for Colon Cancer.

Access to New Clinic Appointments for Patients With Cancer.

Importance: Racial and ethnic disparities have been observed in the outpatient visit rates for specialist care, including cancer care; however, little is known about patients' experience at the critical step of attempting to access new clinic appointments for cancer care. Objective: To determine simulated English-speaking, Spanish-speaking, and Mandarin-speaking patient callers' ability to access new clinic appointments for 3 cancer types (colon, lung, and thyroid cancer) that disproportionately impact Hispanic and Asian populations. Design, Setting, and Participants: This cross-sectional audit study was conducted between November 2021 and March 2023 using 479 clinic telephone numbers that were provided by the hospital general information personnel at 143 hospitals located across 12 US states. Using standardized scripts, trained research personnel assigned to the roles of English-speaking, Spanish-speaking, and Mandarin-speaking patients called the telephone number for a clinic that treats colon, lung, or thyroid cancer to inquire about a new clinic appointment. Data analysis was conducted from June to September 2023. Main Outcomes and Measures: The primary outcome was whether the simulated patient caller was able to access cancer care (binary variable, yes or no), which was defined to include being provided with a clinic appointment date or scheduling information. Multivariable logistic regression analysis was performed to determine factors independently associated with simulated patient callers being able to access cancer care. Results: Of 985 total calls (399 English calls; 302 Spanish calls; 284 Mandarin calls), simulated patient callers accessed cancer care in 409 calls (41.5%). Differences were observed based on language type, with simulated English-speaking patient callers significantly more likely to access cancer care compared with simulated Spanish-speaking and Mandarin-speaking patient callers (English, 245 calls [61.4%]; Spanish, 110 calls [36.4%]; Mandarin, 54 calls [19.0%]; P < .001). A substantial number of calls ended due to linguistic barriers (291 of 586 Spanish or Mandarin calls [49.7%]) and workflow barriers (239 of 985 calls [24.3%]). Compared with English-speaking simulated patient callers, the odds of accessing cancer care were lower for Spanish-speaking simulated patient callers (adjusted odds ratio [aOR], 0.34; 95% CI, 0.25-0.46) and Mandarin-speaking simulated patient callers (aOR, 0.13; 95% CI, 0.09-0.19). Compared with contacting clinics affiliated with teaching hospitals, callers had lower odds of accessing cancer care when contacting clinics that were affiliated with nonteaching hospitals (aOR, 0.53; 95% CI, 0.40-0.70). Conclusions and Relevance: In this cross-sectional audit study, simulated patient callers encountered substantial barriers when attempting to access clinic appointments for cancer care. These findings suggest that interventions focused on mitigating these barriers are necessary to increase access to cancer care for all patients.

Impact of patient, hospital, and operative characteristics relative to social determinants of health: Compliance with National Comprehensive Cancer Network guidelines for colon cancer.

BACKGROUND: Despite an established association with improved patient outcomes, compliance with National Comprehensive Cancer Network (NCCN) guidelines remains suboptimal. We sought to assess the effect of patient characteristics (PCs), operative characteristics (OCs), hospital characteristics (HCs), and social determinants of health (SDoH) on noncompliance with NCCN guidelines for colon cancer. METHODS: Patients treated for stage I to III colon cancer from 2004 to 2017 were identified from the National Cancer Database. Multilevel multivariate regression analysis was performed to identify factors associated with receipt of NCCN-compliant care and quantify the proportion of variance explained by PCs, OCs, HCs, and SDoH. RESULTS: Among 468,097 patients with colon cancer treated across 1319 hospitals, 1 in 4 patients did not receive NCCN-compliant care (122,170 [26.1%]). On regression analysis, older age (odds ratio [OR], 0.96; 95% CI, 0.96-0.96), female sex (OR, 0.97; 95% CI, 0.96-0.99), Black race (OR, 0.96; 95% CI, 0.94-0.98), higher Charlson-Deyo score (OR, 0.84; 95% CI, 0.82-0.86), tumor stage ≥II (OR, 0.42; 95% CI, 0.40-0.44), and tumor grade ≥ 3 (OR, 0.33; 95% CI, 0.32-0.34) were associated with lower odds of receiving NCCN-compliant care (all P values <.05). Higher hospital volume (OR, 1.02; 95% CI, 1.02-1.03), minimally invasive or robotic surgical approach (OR, 1.26; 95% CI, 1.23-1.29), adequate (≥12) lymph node assessment (OR, 3.46; 95% CI, 3.38-3.53), private insurance status (OR, 1.33; 95% CI, 1.26-1.40), Medicare insurance status (OR, 1.42; 95% CI, 1.35-1.49), and higher educational status (OR, 1.06; 95% CI, 1.02-1.09) were associated with higher odds of receiving NCCN-compliant care (all P values <.05). Overall, PCs contributed 36.5%, HCs contributed 1.3%, and OCs contributed 12.9% to the variation in guideline-compliant care, while SDoH contributed only 3.6% of the variation in receipt of NCCN-compliant care. CONCLUSION: The variation in NCCN-compliant care among patients with colon cancer was largely attributable to patient- and surgeon-level factors, whereas SDoH were associated with a smaller proportion of the variation.

Dual-mRNA Delivery Using Tumor Cell Lysate-Based Multifunctional Nanoparticles as an Efficient Colon Cancer Immunogene Therapy.

Background: Messenger RNA (mRNA)-based immunogene therapy holds significant promise as an emerging tumor therapy approach. However, the delivery efficiency of existing mRNA methods and their effectiveness in stimulating anti-tumor immune responses require further enhancement. Tumor cell lysates containing tumor-specific antigens and biomarkers can trigger a stronger immune response to tumors. In addition, strategies involving multiple gene therapies offer potential optimization paths for tumor gene treatments. Methods: Based on the previously developed ideal mRNA delivery system called DOTAP-mPEG-PCL (DMP), which was formed through the self-assembly of 1.2-dioleoyl-3-trimethylammonium-propane (DOTAP) and methoxypoly (ethylene glycol)-b-poly (ε-caprolactone) (mPEG-PCL), we introduced a fused cell-penetrating peptide (fCPP) into the framework and encapsulated tumor cell lysates to form a novel nanovector, termed CLSV system (CLS: CT26 tumor cell lysate, V: nanovector). This system served a dual purpose of facilitating the delivery of two mRNAs and enhancing tumor immunogene therapy through tumor cell lysates. Results: The synthesized CLSV system had an average size of 241.17 nm and a potential of 39.53 mV. The CLSV system could not only encapsulate tumor cell lysates, but also deliver two mRNAs to tumor cells simultaneously, with a transfection efficiency of up to 60%. The CLSV system effectively activated the immune system such as dendritic cells to mature and activate, leading to an anti-tumor immune response. By loading Bim-encoded mRNA and IL-23A-encoded mRNA, CLSV/Bim and CLSV/IL-23A complexes were formed, respectively, to further induce apoptosis and anti-tumor immunity. The prepared CLSV/dual-mRNA complex showed significant anti-cancer effects in multiple CT26 mouse models. Conclusion: Our results suggest that the prepared CLSV system is an ideal delivery system for dual-mRNA immunogene therapy.

Turning Waste into Wealth: A Potent Sono-Immune Strategy Based on Microcystis.

Currently, sonodynamic therapy (SDT) has limited therapeutic outcomes and immune responses, highlighting the urgent need for enhanced strategies that can stimulate robust and long-lasting antitumor effects. Microcystis, a notorious microalga, reveals the possibility of mediating SDT owing to the presence of gas vesicles (GVs) and phycocyanin (PC). Herein, a nontoxic strain of Microcystis elabens (labeled Me) is developed as a novel agent for SDT because it generates O2 under red light (RL) illumination, while GVs and PC act as cavitation nuclei and sonosensitizers, respectively. Moreover, algal debris is released after ultrasound (US) irradiation, which primes the Toll-like receptor pathway to initiate a cascade of immune responses. This sono-immune strategy inhibits CT26 colon tumor growth largely by promoting dendritic cell (DC) maturation and cytotoxic T-cell activation. After combination with the immune checkpoint blockade (ICB), the therapeutic outcome is further amplified, accompanied by satisfactory abscopal and immune memory effects; the similar potency is proven in the "cold" 4T1 triple-negative breast tumor. In addition, Me exhibits good biosafety without significant acute or chronic toxicity. Briefly, this study turns waste into wealth by introducing sono-immunotherapy based on Microcystis that achieved encouraging therapeutic effects on cancer, which is expected to be translated into the clinic.