Hepatocellular carcinoma (HCC) is a major global health issue characterized by poor prognosis and complex tumor biology. One of the critical components of the HCC tumor microenvironment (TME) is tumor-associated macrophages (TAMs), which play a pivotal role in modulating tumor growth, immune evasion, and metastasis. Macrophages are divided into two major subtypes: pro-inflammatory M1 and anti-inflammatory M2, both of which may exist in TME with altered function and proportion. The anti-inflammatory M2 macrophages are further subdivided into four distinct immune suppressive subsets. TAMs are generally counted as M2-like macrophages with altered immune suppressive functions that exert a significant influence on both cancer progression and the ability of tumors to escape immune surveillance. Their involvement in modulating immune responses via different mechanisms at the local and systemic levels has made them a key target for therapeutic interventions seeking to enhance treatment outcomes. How TAMs’ depletion influences immune responses in cancer is the primary interest in cancer immunotherapies. The purpose of this review is to delve into the recent progress made in TAM-targeting therapies. We will explore the current theories, benefits, and challenges associated with TAMs’ depletion or inhibition. The manuscript concludes with future directions and potential implications for clinical practice.

The discovery of BRCA1 and BRCA2 in the 1990s revolutionized the way we research and treat breast, ovarian, and pancreatic cancers. In the case of pancreatic cancers, germline mutations occur in about 10–20% of patients, with mutations in BRCA1 and BRCA2 being the most common. BRCA genes are critical in DNA repair pathways, particularly in homologous recombination, which has a serious impact on genomic stability and can contribute to cancerous cell proliferation. However, BRCA1 also plays a fundamental role in cell cycle checkpoint control, ubiquitination, control of gene expression, and chromatin remodeling, while BRCA2 also plays a role in transcription and immune system response. Therefore, mutations in these genes lead to multiple defects in cells that may be utilized when treating cancer. BRCA mutations seem to confer a prognostic benefit with an improved overall survival due to differing underlying biology. These mutations also appear to be a predictive marker, with patients showing increased sensitivity to certain treatments, such as platinum chemotherapy and PARP inhibitors. Olaparib is currently indicated for maintenance therapy in metastatic PDAC after induction with platinum-based chemotherapy. Resistance has been found to these therapies, and with a 10.8% five-year OS, novel therapies are desperately needed.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide. HCC tumor development and treatment resistance are impacted by changes in the microenvironment of the hepatic immune system. Immunotherapy has the potential to improve response rates by overcoming immune tolerance mechanisms and strengthening anti-tumor activity in the tumor microenvironment. In this review, we characterize the impact of immunotherapy on outcomes of advanced HCC, as well as the active clinical trials evaluating novel combination immunotherapy strategies. In particular, we discuss the efficacy of atezolizumab and bevacizumab as demonstrated in the IMbrave150 study, which created a new standard of care for the front-line treatment of advanced HCC. However, there are multiple ongoing trials that may present additional front-line treatment options depending on their efficacy/toxicity results. Furthermore, the preliminary data on the application of chimeric antigen receptor (CAR-T) cell therapy for treatment of HCC suggests this may be a promising option for the future of advanced HCC treatment.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related morbidity and mortality around the world. Despite advances in surgery, chemotherapy, and targeted therapies, the prognosis for patients with metastatic or advanced CRC remains poor. Immunotherapies comprising immune checkpoint inhibitors showed disappointing responses in metastatic CRC (mCRC). However, cellular immunotherapy, specifically using classical dendritic cells (cDCs), may hold unique promise in immune recognition for CRC antigens. cDCs are substantial players in immune recognition and are instrumental in orchestrating innate and adaptive immune responses by processing and presenting tumor antigens to effector cells. Natural killer T (NKT) cells are insufficiently studied but unique effector cells because of their ability to bridge innate and adaptive immune reactions and the crosstalk with dendritic cells in cancer. This review explores the therapeutic potential of using both cDCs and NKT cells as a synergistic therapy in CRC, focusing on their biological roles, strategies for harnessing their capabilities, clinical applications, and the challenges within the tumor microenvironment. Both cDCs and NKT cells can be used as a new effective approach for cell-based therapies in cancers to provide a new hope for CRC patients that are challenging to treat.

Cholangiocarcinoma (CCA) is a heterogenous group of malignancies originating in the biliary tree, and associated with poor prognosis. Until recently, treatment options have been limited to surgical resection, liver-directed therapies, and chemotherapy. Identification of actionable genomic alterations with biomarker testing has revolutionized the treatment paradigm for these patients. However, several challenges exist to the seamless adoption of precision medicine in patients with CCA, relating to a lack of awareness of the importance of biomarker testing, hurdles in tissue acquisition, and ineffective collaboration among the multidisciplinary team (MDT). To identify gaps in standard practices and define best practices, multidisciplinary hepatobiliary teams from the University of California (UC) Davis and UC Irvine were convened; discussions of the meeting, including optimal approaches to tissue acquisition for diagnosis and biomarker testing, communication among academic and community healthcare teams, and physician education regarding biomarker testing, are summarized in this review.

Background: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year overall survival rate of 10%. In November 2018, NCCN recommended that all patients with PDAC receive genetic counseling (GC) and germline testing regardless of family history. We hypothesized that patients with PDAC were more likely to be referred for testing after this change to the guidelines, regardless of presumed predictive factors, and that compliance would be further improved following the implementation of a hereditary cancer clinic (HCC). Methods: We conducted a single-institution retrospective analysis of patients diagnosed with PDAC from June 2017 through December 2021 at University of California, Irvine. We compared rates of genetics referral among patients in different diagnostic eras: the 18-month period before the NCCN Guideline change (pre-NCCN era: June 2017 through November 2018), 14 months following the change (post-NCCN era: December 2018 through January 2020), and 18 months after the creation of an HCC (HCC era: June 2020 through December 2021). Family and personal cancer history, genetics referral patterns, and results of GC were recorded. Data were compared using chi-square, Fisher exact, and multivariate analyses. Results: A total of 335 patients were treated for PDAC (123 pre-NCCN, 109 post-NCCN, and 103 HCC) at University of California, Irvine. Demographics across groups were comparable. Prior to the guideline changes, 30% were referred to GC compared with 54.7% in the post-NCCN era. After the implementation of the HCC, 77.4% were referred to GC (P<.0001). The odds ratio (OR) for referral to GC among patients with a positive family history of cancer progressively decreased following the change (pre-NCCN era: OR, 11.90 [95% CI, 3.00–80.14]; post-NCCN era: OR, 3.39 [95% CI, 1.13–10.76]; HCC era: OR, 3.11 [95% CI, 0.95–10.16]). Conclusions: The 2018 updates to the NCCN Guidelines for PDAC recommending germline testing for all patients with PDAC significantly increased GC referral rates at our academic medical center. Implementation of an HCC further boosted compliance with guidelines.