ObjectiveTo explore the effect of Tongxie Yaofang on the immune microenvironment of colorectal cancer in mice under chronic stress and the underlying mechanism. MethodA total of 40 male SPF BABL/C mice were randomized into normal group， stress group， Tongxie Yaofang group （13.65 g·kg^-1）， and Tongxie Yaofang-stress group （13.65 g·kg^-1）， with 10 in each group. Chronic restraint stress was induced in mice and administration （ig） of Tongxie Yaofang began after 7 days of stress. On the 14^th day， forced swim and tail suspension tests were used to examine the behavioral changes of mice after stress and the subcutaneous colorectal tumor was implanted in each group of mice. The effect of this prescription on the body mass and tumor volume of mice was observed. After the last administration， mouse serum and tumor samples were collected. The content of T lymphocytes （CD3⁺， CD4⁺， CD8⁺， and CD4⁺/CD8⁺） in tumor was detected by immunohistochemistry and flow cytometry and levels of corticosterone （CORT） in peripheral blood， and interleukin （IL）-2， interferon-γ （IFN-γ）， IL-6， and IL-10 in the serum were determined by enzyme-linked immunosorbent assay （ELISA）. The protein expression of inhibitor of nuclear factor-κB（IκB） kinase α/β （IKKα/β）， nuclear factor-κB （NF-κB）α （IκBα）， NF-κB p65， and phosphorylated （p）-NF-κB p65 was measured by Western blot. ResultCompared with the normal group， the stress group had large tumor volume （P<0.05）， low content of CD3⁺， CD4⁺， and CD4⁺/CD8⁺ （P<0.05， P<0.01）， high content of CD8⁺， low content of T helper 1 （Th1）-secreted IFN-γ （P<0.05）， high content of T helper 2 （Th2）-secreted IL-10 （P<0.05） and CORT （P<0.05）， high protein expression of p-NF-κB p65， NF-κB p65， and IKKα/β （P<0.05）， and low protein expression of IκBα （P<0.05）. Compared with the normal group， the Tongxie Yaofang group showed slow tumor growth， high content of CD3⁺， CD4⁺， and CD4⁺/CD8⁺ （P<0.01）， low content of CD8⁺ （P<0.05）， high content of Th1-secreted IL-2 and IFN-γ （P<0.05）， low content of Th2-secreted IL-6 and IL-10 （P<0.05）， low content of CORT， low protein expression of p-NF-κB p65， NF-κB p65， and IKKα/β （P<0.05）， and high protein expression of IκBα （P<0.01）. Tongxie Yaofang-stress group demonstrated slower tumor growth， higher content of CD3⁺， CD4⁺， and CD4⁺/CD8⁺ （P<0.01）， smaller content of CD8⁺ （P<0.05）， higher content of IL-2 and IFN-γ （P<0.05）， lower content of IL-6， IL-10 （P<0.05）， and CORT （P<0.05）， lower protein expression of p-NF-κB p65， NF-κB p65， and IKKα/β （P<0.05，P<0.01）， and higher protein expression of IκBα （P<0.01） than the stress group. ConclusionTongxie Yaofang can delay the growth of colorectal cancer under chronic stress and alleviate the deterioration of the immune microenvironment， possibly by inhibiting NF-κB signaling pathway， regulating the function of T lymphocyte subsets， and thus suppressing the secretion of pro-inflammatory factors.

ObjectiveTo observe the effect of berberine combined with evodiamine on the migration and invasion of colorectal cancer HCT116 and RKO cells and to explore the underlying mechanism. Methodcell counting kit-8 （CCK-8） assay was used to examine the proliferation of HCT116 and RKO cells treated by berberine （30 μmol·L^-1）， evodiamine （0.8 μmol·L^-1）， and combination of two （30 μmol·L^-1+0.8 μmol·L^-1）， respectively. Scratch assay and Transwell assay were employed to detect the migration and invasion of HCT116 and RKO cells treated with berberine， evodiamine， and the combination， separately. In addition， the protein expression of epithelial cadherin （E-cadherin）， neural cadherin （N-cadherin）， phosphatidylinositol 3-kinase （PI3K）， and protein kinase B （Akt） in HCT116 and RKO cells treated with the berberine， evodiamine， and the combination was respectively measured by Western blot. ResultCompared with the blank group， berberine alone and evodiamine alone had no significant inhibitory effect on the proliferation， migration， and invasion of HCT116 and RKO cells， while the combination showed significant inhibition （P<0.01）. Berberine alone and evodiamine alone had no remarkable influence on the expression of PI3K， N-cadherin， and E-cadherin in HCT116 and RKO cells， but the combination significantly reduced the expression of PI3K and N-cadherin （P<0.01） and increased the expression of E-cadherin （P<0.01） in HCT116 and RKO cells. Evodiamine alone also significantly suppressed the expression of Akt protein in HCT116 and RKO cells （P<0.05）， but the suppression was weaker than that of the combination. ConclusionThe combination of berberine and evodiamine can significantly inhibit the migration and invasion of colorectal cancer HCT116 and RKO cells and the two show synergy. The mechanism is the likelihood that the combination down-regulates the expression of PI3K and Akt.

Since the approval of gemtuzumab ozogamicin, an antibody–drug conjugate (ADC) targeting CD33 in 2000, 13 ADC drugs have been approved by the FDA. Although these drugs have clearly improved the survival of patients with various types of advanced cancers, their significant toxicity has compromised their therapeutic benefits. The adverse reactions of ADC drugs are complex and include on-target and off-target toxicities, where the payload drug is a determining factor. Antibody and linker may also affect the degree of toxicity. Combination therapy becomes an important strategy in anticancer treatment because of its increased efficiency, but treatment-related adverse reactions also increase accordingly. This review comprehensively analyzes the toxicity mechanisms of current ADC drugs and proposes various optimization strategies, including but not limited to optimizing linker molecules, upgrading antibody design, and changing drug administration strategies, to improve the overall safety profile of ADC drugs.