Colorectal cancer (CRC) is one of the most common and deadliest forms of cancer. Myeloid Cell Leukemia 1 (MCL1), a pro-survival member of the Bcl-2 protein family is associated with chemo-resistance in CRC. The ability of MCL1 to inhibit apoptosis by binding to the BH3 domains of pro-apoptotic Bcl-2 family members is a well-studied means by which this protein confers resistance to multiple anti-cancer therapies. We found that specific DNA damaging chemotherapies promote nuclear MCL1 translocation in CRC models. In p53^null CRC, this process is associated with resistance to chemotherapeutic agents, the mechanism of which is distinct from the classical mitochondrial protection. We previously reported that MCL1 has a noncanonical chemoresistance capability, which requires a novel loop domain that is distinct from the BH3-binding domain associated with anti-apoptotic function. Herein we disclose that upon treatment with specific DNA-damaging chemotherapy, this loop domain binds directly to alpha-enolase which in turn binds to calmodulin; we further show these protein−protein interactions are critical in MCL1’s nuclear import and chemoresistance. We additionally observed that in chemotherapy-treated p53^−/− CRC models, MCL1 nuclear translocation confers sensitivity to Bcl-xL inhibitors, which has significant translational relevance given the co-expression of these proteins in CRC patient samples. Together these findings indicate that chemotherapy-induced MCL1 translocation represents a novel resistance mechanism in CRC, while also exposing an inherent and targetable Bcl-xL co-dependency in these cancers. The combination of chemotherapy and Bcl-xL inhibitors may thus represent a rational means of treating p53^−/− CRC via exploitation of this unique MCL1-based chemoresistance mechanism.

Cholangiocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts, with poor prognosis and limited treatment options. Traditional therapies, such as surgery, chemotherapy, and radiation, have shown limited efficacy, especially in advanced cases. Recent advancements in immunotherapy, particularly T cell-based therapies like chimeric antigen receptor T (CAR T) cells, tumor-infiltrating lymphocytes (TILs), and T cell receptor (TCR)-based therapies, have opened new avenues for improving outcomes in CCA. This review provides a comprehensive overview of the current state of T cell therapies for CCA, focusing on CAR T cell therapy. It highlights key challenges, including the complex tumor microenvironment and immune evasion mechanisms, and the progress made in preclinical and clinical trials. The review also discusses ongoing clinical trials targeting specific CCA antigens, such as MUC1, EGFR, and CD133, and the evolving role of precision immunotherapy in enhancing treatment outcomes. Despite significant progress, further research is needed to optimize these therapies for solid tumors like CCA. By summarizing the most recent clinical results and future directions, this review underscores the promising potential of T cell therapies in revolutionizing CCA treatment.

Cancer immunotherapy has transformed the global oncology landscape, offering durable responses across malignancies once considered untreatable. In Asia and Southeast Asia, regions facing a rising cancer burden, countries such as Malaysia are progressively integrating immunotherapeutic approaches, including immune checkpoint inhibitors and CAR-T cell therapies. Regional progress is supported by investments in research infrastructure, expanding clinical trial participation, and cross-border regulatory collaboration. However, significant challenges persist. Diverse genetic and epidemiological profiles complicate treatment generalizability, while disparities in healthcare access, limited biomarker validation, and high costs restrict widespread implementation, particularly in low- and middle-income settings. In Southeast Asia, including Malaysia, these challenges are intensified by urban-rural disparities in healthcare access and financial limitations. However, emerging opportunities such as biomarker-informed precision immunotherapy, artificial intelligence-enabled treatment personalization, expanded telemedicine services, and enhanced access frameworks offer promising pathways forward. This review highlights the current landscape, ongoing challenges, and future prospects of cancer immunotherapy in Asia and Southeast Asia, with a particular focus on Malaysia’s growing role in this evolving field. Cross-regional cooperation, regulatory harmonization, and personalized treatment strategies are crucial for equitable access to cancer therapies across this region. By synthesizing fragmented and underrepresented evidence from Southeast Asia within a broader Asia-focused immunotherapy framework, this review aims to provide a consolidated reference that can guide future research prioritization, strengthen regional policy development, and support the design of more inclusive and scalable immunotherapy implementation strategies.