Impacts caused by cancer and associated treatment may change with time. The objective of this study is to examine the change trajectory of symptom distress, coping strategies, and spiritual wellbeing in colorectal cancer patients during chemotherapy and to further examine the predictors of spiritual wellbeing. A prospective longitudinal repeated measures study design was employed. A total of 97 patients undergoing chemotherapy for the first time were enrolled. A structured questionnaire was used to collect data at three timepoints, which were before chemotherapy (T0), during chemotherapy (T1: 3 months after T0), and after chemotherapy (T2: 6 months after T0). The results of this study show that patients have significantly lower spiritual wellbeing and significantly higher symptom distress during chemotherapy treatment (T1). Family support (B = 0.39, p = 0.007) and problem-focused coping strategies (B = 0.47, p = 0.001) are significant predictors of spiritual wellbeing before chemotherapy (T0). Symptom distress (B = −0.18, p = 0.048) and problem-focused coping strategies (B = 0.26, p = 0.028) are significant predictors of spiritual wellbeing during chemotherapy (T1). The results provide care recommendations for different stages of chemotherapy to help to achieve more precise patient care and improve care quality.

Colorectal cancer (CRC) remains a formidable clinical challenge due to immune escape, metastasis, and resistance to conventional therapies. This study engineered a tumor microenvironment (TME)-responsive platform of orthogonally masked polyethylene glycol (omPEG)-coated solid lipid nanoparticles (SLNs) for targeted combinatorial immunotherapy in EGFR/PD-L1/CTLA-4-dysregulated CRC. The formulation co-delivered NMS-873 (NM), a VCP/p97 inhibitor, to induce endoplasmic reticulum stress (ERS) and proteostasis collapse, together with bispecific PD-L1/CTLA-4 aptamers (P1C4) for dual checkpoint blockade. A complementary SLN formulation encapsulating galunisertib (G) and DNase (DN) degraded neutrophil extracellular traps (NETs) and suppressed tumor-associated neutrophils (TANs), thereby reshaping the immunosuppressive TME. The pH-sensitive omPEG shell preserved peptide ligand activity in circulation and enabled tumor-localized exposure of moieties targeting EGFR, ER, PD-L1, and CXCR2, thereby directing delivery toward CRC cells, tumor-associated macrophages (TAMs), and TANs. NM-induced ERS led to immunogenic cell death, G1 arrest, and apoptosis, while P1C4 co-loading suppressed epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC)-like traits by downregulating N-cadherin/Slug/Snail/Smad and CD44/Oct4/Nanog/c-Myc/MMP-9 and restoring E-cadherin, thereby mitigating tumor migration and aggressiveness. The combinatorial treatment provoked potent antitumor immunity, reactivated dendritic and CD8⁺/CD4⁺ T cells, and enhanced proinflammatory cytokines (IL-1α, IL-2, IL-9, IL-12, IFN-γ, TNF-α, MIP-1β), while suppressing TGF-β, IL-4, IL-5, IL-10, Tregs, TAMs, and TANs. In vivo PET/MRI imaging and immunohistopathological analyses confirmed selective tumor accumulation and effective tumor regression. This peptide-guided, TME-tailored SLN strategy achieves coordinated immune reprogramming, ERS induction, EMT/CSC reversal, NET disruption, and dual checkpoint blockade, offering a clinically translatable platform to overcome chemoimmunotherapy resistance in EGFR/PD-L1/CTLA-4-driven CRC.

Background STAT3 is a transcriptional factor involved in tumorigenesis and the initiation of cancer stemness property. However, the STAT3‐downstream regulatory gene expressions in the formation of colorectal cancer‐derived tumorsphere is obscure. Methods In this study, RNAseq was used to uncover the potential genes involved in the formation of colorectal HCT116‐ and HT29‐derived stem‐like tumorspheres, whereas HCT116 and HT29 overexpressed CD133. Furthermore, STAT3 was knockdowned and analyzed consequently by RNAseq for picking up the STAT3‐mediated genes associated with tumorspheres formation. Then, qPCR was used for validating the expressions of selected driver genes in EGF treated‐ and in STAT3‐knockdowned HT29 cells. Results We found that 654 genes and 646 genes were up‐regulated in HCT116‐ and HT29‐derived tumorspheres, respectively. There were 103 genes simultaneously increased in both colorectal cancer tumorspheres, including STAT3 selected as a driver gene by NetworkAnalyst (https://www.networkanalyst.ca/). Moreover, there were 139 genes down‐regulated in HT29shSTAT3 cells compared to HT29shLuc cells, 12 of the genes were overlapped with the overexpressed 103 genes from tumorspheres, including NDRG1, ALDOC, BHLHE40, ATF3, C6orf223, JUND, ERRFI1, HK2, ITPKA, PLOD2, IDI1, S100A14 . Among them, BHLHE40, ATF3, ERRFI1, ITPKA, and S100A14 were validated and induced by EGF treatment, that were, otherwise, decreased in HT29shSTAT3 cells. Conclusions We found and validated that STAT3 mediated the formation of colorectal cancer stemness tumorspheres, and STAT3‐downstram BHLHE40, ATF3, ERRFI1, ITPKA, and S100A14 may be involved in stemness property.

Background: Colorectal cancer (CRC), particularly the microsatellite-stable (MSS) subtype, remains largely unresponsive to immune checkpoint inhibitors (ICIs) due to immune escape, tumor-associated macrophage (TAM) enrichment, and cytokine-driven suppression that sustain a TAM-dominant tumor microenvironment (TME). To overcome these barriers, a pH-responsive solid lipid nanoparticle (SLN) system was engineered to co-deliver CB-5083 (a VCP/p97 inhibitor), miR-142 (a PD-L1-targeting microRNA), and imiquimod (R, a TLR7 agonist) for spatially confined induction of endoplasmic reticulum stress (ERS) and immune reprogramming in MSS CRC. Methods: The SLNs were coated with PEG–PGA for pH-triggered de-shielding and functionalized with PD-L1- and EGFR-binding peptides plus an ER-homing peptide, enabling tumor-selective and subcellular targeting. Results: The nanoplatform displayed acid-triggered PEG–PGA detachment, selective CRC/TAM uptake, and ER localization. CB-mediated VCP inhibition activated IRE1α/XBP1s/LC3II, PERK/eIF2α/ATF4/CHOP, and JNK/Beclin signaling, driving apoptosis and autophagy, while miR-142 suppressed PD-L1 expression and epithelial–mesenchymal transition markers. R facilitated dendritic cell maturation and M1 polarization. Combined CB + miR + R/SLN-CSW suppressed IL-17, G-CSF, and CXCL1, increased infiltration of CD4⁺ and CD8⁺ T cells, reduced Tregs and M2-TAMs, and inhibited tumor growth in CT-26 bearing mice. The treatment induced immunogenic cell death, reprogramming the TME into a T cell-permissive state and conferring resistance to tumor rechallenge. Biodistribution analysis confirmed tumor-preferential accumulation with minimal off-target exposure, and biosafety profiling demonstrated low systemic toxicity. Conclusions: This TME-responsive nanoplatform therefore integrates ERS induction, checkpoint modulation, and cytokine suppression to overcome immune exclusion in MSS CRC, representing a clinically translatable strategy for chemo-immunotherapy in immune-refractory tumors.