Nanoprodrug targeting tumor-associated intracellular bacteria enhances colorectal cancer immunotherapy

​Colorectal cancer treatment has entered the immunotherapy era. While immunotherapy has markedly improved outcomes for microsatellite instability-high (MSI-H) patients, the majority of microsatellite stable (MSS) cases remain unresponsive to immune monotherapy, leading to distinct "cold" and "hot" tumor response states. Transforming "cold tumors" into "hot tumors" is a pivotal research focus. Drug repurposing combined with immunotherapy emerges as a novel strategy that enhances efficacy and reduces adverse effects by repurposing existing drugs, while addressing comorbidities. This approach offers cost-effective and rapid clinical translation. This review systematically explores the potential and challenges of this synergistic approach. In the future, efforts can be focused on initiating prospective studies among the neoadjuvant treatment population, improving drug delivery approaches with the help of materials science, and identifying immune-favorable subgroups. Additionally, considering the characteristics of comorbidity between chronic diseases and colorectal cancer against the backdrop of China's aging society, large-scale multicenter retrospective analyses should be conducted to screen drugs, clarify the interactions between chronic disease medications and immune checkpoint inhibitors (ICIs). This aims to provide more precise combined treatment guidance for colorectal cancer patients, especially those with comorbid chronic diseases, and help achieve the goals of organ preservation and quality of life improvement for more patients.

Preclinical assessment of genetically modified exosomes for colorectal cancer immunotherapy.

Colorectal cancer (CRC) is considered to be a heterogeneous disease with different molecular subtypes based on the expression status of mismatch repair (MMR) e.g. It is well known that tumours with mismatch repair deficiency (dMMR) are associated with better prognosis, as well as a more effective response to immunotherapy. In this case report, a patient is diagnosed with three new dMMR tumors in the colon 3,5 years after successful treatment with immunotherapy for metastatic CRC. Until now, retreatment with immunotherapy has not been described in the literature, and this case report describes the advantages and disadvantages from this perspective.

IntroductionIndividuals diagnosed with colorectal cancer (CRC) frequently confront a grave prognosis and exhibit poor responses to conventional treatment regimens. Immunotherapy, notably modalities centered on natural killer (NK) cells, represents a burgeoning frontier in the management of CRC. This study developed a validated prognostic model using NK-associated long non-coding RNAs (lncRNAs) to predict CRC outcomes.MethodsIntegrating single-cell RNA-seq (GSE146771_Smartseq2) and TCGA-COAD/READ bulk transcriptomic data, we identified NK-specific genes and correlated lncRNAs. A multi-step analytical approach—including univariate Cox regression for preliminary screening, LASSO regression to minimize overfitting, and multivariate Cox regression for final model optimization—yielded a robust 16-lncRNA prognostic signature with high predictive accuracy. ResultsThis model demonstrated robust predictive performance across the training set, validation set, and 76 independent clinical samples. Mechanistic investigations revealed that AC010319.3 is highly expressed in NK cells, where it attenuates NK cell cytotoxicity by suppressing the expression of IFN-γ and granzyme B, thereby promoting the proliferation and invasion of CRC cells.DiscussionThis study systematically delineates the regulatory role of NK-associated lncRNAs within the CRC immune microenvironment, offering novel molecular targets and stratification strategies for CRC immunotherapy.

Transforming growth factor β (TGF-β) signaling in the tumor microenvironment predicts resistance to immune checkpoint blockade (ICB). While TGF-β inhibition enhances ICB efficacy in murine cancer models, clinical trials have yet to demonstrate benefit, underscoring the need to better understand its immunoregulatory roles across disease contexts. Using mouse models of advanced colorectal cancer and patient-derived data, we demonstrate that TGF-β impairs antitumor immunity at multiple levels in liver metastases. It acts directly on T cells to block recruitment of peripheral memory CD8+ T cells, thereby limiting the effectiveness of ICB. Concurrently, TGF-β instructs tumor-associated macrophages to suppress clonal expansion of newly arrived T cells by inducing SPP1 expression. This extracellular matrix protein promotes collagen deposition and accumulation of tumor-associated macrophages and fibroblasts, ultimately driving ICB resistance. Our findings reveal how TGF-β coordinates immunosuppressive mechanisms across innate and adaptive immune compartments to promote metastasis, offering new avenues to improve immunotherapy in colorectal cancer.

In colorectal cancer (CRC), the upregulation of Candida albicans (C. albicans) abundance significantly promotes tumor progression and exacerbates immunosuppression. In this study, we demonstrate that candidalysin-induced macrophage pyroptosis contributes to the immunosuppressive tumor microenvironment (TME). Conversely, the neutralizing peptide of candidalysin, isolated via phage display, effectively protects macrophages from pyroptosis. Based on this, we constructed an epigenetic inhibitor-loaded nanomodulator to target the interaction between C. albicans and macrophages. To ensure precise targeting of intraspecific morphological differences, the nanomodulator is covered with the C. albicans pretreated macrophage membranes. The nanomodulator exhibits the ability to protect macrophages from pyroptosis and reprograms the metabolic and immune response of macrophages, while the epigenetic inhibitor upregulates tumor self-antigen presentation. In vivo, the nanomodulator has been shown to effectively sustain macrophage activation within the TME and promotes a robust IL-17-mediated immune response. Meanwhile, the nanomodulator exhibited excellent immune memory effects and effectively synergized with immune checkpoint blockade therapy in an orthotopic CRC model. This approach of manipulating the C. albicans-macrophage crosstalk to augment therapeutic efficacy in CRC offers promising insights for the clinical management of CRC.

Endoplasmic reticulum-mitochondria dual-targeting nanoplatform suppresses cancer stemness and enhances colorectal cancer immunotherapy.

A transformer-based pathomics model using endoscopic biopsy WSIs for predicting pathological complete response to preoperative immunotherapy in colorectal cancer.

The current status of immunotherapy in colorectal cancer: A systematic review

Research progress on gut microbiota in colorectal cancer immunotherapy.

The dawn of immunotherapy in mismatch repair proficient colorectal cancer.

Mitochondria-targeted hybrid nanovesicles trigger immunogenic cell death and remodel tumor neutrophils for enhanced colorectal cancer immunotherapy.

Biomineralized Cu-Disulfiram nanoparticles Potentiate Colorectal cancer immunotherapy through synergistic cuproptosis and apoptosis

Simple SummaryMicrosatellite instability-high (MSI-H) colon cancer is characterized by impaired DNA mismatch repair and robust responsiveness to immune checkpoint inhibition. However, the optimal management of patients with isolated peritoneal metastases (iPM), a site of spread associated with historically poor prognosis, remains poorly defined. Leveraging national real-world data, this study demonstrates that immunotherapy is associated with significantly improved survival compared to chemotherapy in patients with MSI-H colon cancer and iPM. Importantly, the combination of immunotherapy and surgical resection resulted in the greatest survival benefit. These findings challenge conventional paradigms that discourage surgery in metastatic disease and support a multimodal treatment strategy for this biologically distinct and clinically challenging patient population. The results highlight the need for prospective trials to define optimal sequencing and integration of surgery and immunotherapy in MSI-H colorectal cancer with peritoneal involvement.Background: Microsatellite instability-high (MSI-H) colon cancer with isolated peritoneal metastases (iPM) represents a molecularly and anatomically distinct clinical subset with limited evidence to guide treatment. Given the unique immunogenic profile of MSI-H tumors and the historically poor prognosis of peritoneal dissemination, we evaluated the association of immunotherapy, chemotherapy, and surgery with survival outcomes in this population. Methods: Using the National Cancer Database, we identified patients with MSI-H colon cancer and iPM diagnosed between 2016–2021. Patients were stratified by systemic therapy type (immunotherapy, chemotherapy, combination) and surgical resection status. Kaplan–Meier and multivariable Cox regression analyses were used to assess overall survival (OS). Results: Among 598 patients, 22% received systemic treatment with immunotherapy and 76% underwent surgical resection. Immunotherapy was associated with significantly longer median OS compared to chemotherapy (33 vs. 18 months, p < 0.001). On multivariable analysis, immunotherapy remained independently associated with improved survival (HR: 0.46; p < 0.001). Surgical resection of the primary tumor with (HR: 0.40; p < 0.001) or without metastatectomy (HR: 0.41; p < 0.001) was associated with longer survival, and the combination of surgery and immunotherapy yielded the greatest survival benefit. Conclusions: Patients with MSI-H colon cancer and iPM treated with immunotherapy had significantly improved survival, compared to chemotherapy. Surgical resection combined with immunotherapy is associated with the greatest survival benefit, supporting a multimodal approach. These findings provide real-world evidence supporting integration of immunotherapy and surgery in this molecularly and anatomically distinct population.

Colorectal cancer is an oncological disease with high incidence and social significance. Despite advances in diagnostics and the multimodal approach to treatment, the prognosis for patients with advanced or metastatic disease remains poor. This necessitates a more in-depth study of tumor biology and the elucidation of various important pathogenetic factors for the development of the disease. Knowledge of genomic instability pathways enables tumor typing and the application of effective personalized treatment. Traditional therapeutic approaches are often associated with significant toxicity and resistance, which requires the search for more effective and tolerable medicinal products. The current article aims to review contemporary achievements and future directions in the field of immunotherapy for colorectal cancer, with a focus on mechanisms of action, clinical outcomes, and strategies for overcoming resistance.

PurposeTo identify the clinical and molecular factors that effectively predict pathological complete response (pCR) and assess the safety of patients receiving neoadjuvant combination immunotherapy.MethodsThis retrospective study evaluated 81 patients with colorectal cancer (CRC) at a Chinese tertiary center between 2015 and 2023. The cohort included 24 patients with deficient mismatch repair (dMMR) and 57 patients with proficient mismatch repair (pMMR) tumors. Patients were treated with a neoadjuvant combination of immunotherapy and surgery.ResultsWe divided 81 patients into pCR (40.7%) and non-pCR (59.3%) groups. The factors significantly associated with a higher pCR rate after neoadjuvant combination immunotherapy were younger age, low carcinoembryonic antigen (CEA) level, high tumor mutational burden (TMB) level before treatment, clinical stage III, absence of lymph node metastasis before treatment, MSI-H level, dMMR, and pole status mutation. Preoperative combined chemotherapy and targeted therapy also influenced the pCR rate. Neoadjuvant combination immunotherapy showed an overall adverse event (AE) rate of 29.6%, with none of grades 3‒4. Surgery-related adverse reactions (srAEs) were also absent for grades 3‒4; 14 of the 81 patients experienced grade 1‒2 AEs.ConclusionNeoadjuvant combination immunotherapy resulted in a favorable pCR rate in patients with CRC. Young age, pretreatment CEA level, TMB level, clinical stage, lymph node metastasis, MSI, MMR, and pole status can be used as indicators of the efficacy of neoadjuvant combination immunotherapy. The incidence of AEs from neoadjuvant combination immunotherapy and surgery was low, indicating that this regimen is safe and feasible.

The current status of immunotherapy in colorectal cancer: A systematic review.

This study introduces the Sono@NAT10 nanorobot for colorectal cancer (CRC) immunotherapy, designed to target NAT10 condensates in macrophages. Sono@NAT10, enclosed in a macrophage membrane using a metal-organic framework, shows stability under acidic conditions and releases NAT10 siRNA upon ultrasound activation. Flow cytometry and confocal imaging confirm effective macrophage targeting. Sequencing and proteomics reveal that NAT10 regulates SRSF2 protein stability, thereby promoting the transition of macrophages from the M2 to the M1 phenotype. In a CRC mouse model, Sono@NAT10 combined with anti-PD-1 (CD279) antibody inhibited tumor growth and enhances survival. These findings demonstrate the potential of Sono@NAT10 as a novel immunotherapeutic strategy for CRC by modulating NAT10 phase separation, providing a foundation for further exploration of its clinical application.

Background: Aryl hydrocarbon receptor (AhR) is a transcription factor that is involved in the regulation of immunity. AhR inhibits T cell activation in tumors, which induces immune suppression in the blood and solid tumors. We identified effective small-molecule AhR antagonists for cancer immunotherapy. Methods: A new series of pyrazolopyrimidine derivatives was synthesized and evaluated for AhR antagonistic activity. Results: Compound 7k exhibited significant antagonistic activity against AhR in a transgenic zebrafish model. In addition, 7k exhibited good AhR antagonist activity, with a half-maximal inhibitory concentration (IC50) of 13.72 nM. Compound 7k showed a good pharmacokinetic profile with an oral bioavailability of 71.0% and a reasonable half-life of 3.77 h. Compound 7k selectively exerted anti-proliferative effects on colorectal cancer cells without affecting normal cells, concurrently suppressing the expression of AhR-related genes and the PD-1/PD-L1 signaling pathway. Compound 7k exhibited potent antitumor activity in syngeneic colorectal cancer models. Importantly, the combination of anti-PD1 and compound 7k enhanced antitumor immunity by augmenting cytotoxic T lymphocyte (CTL)-mediated activity. Conclusions: Collectively, a new pyrazolopyrimidine derivative, 7k, shows promise as a potential therapeutic agent for treating colorectal cancer.