This review aims to address the bottleneck of antigen heterogeneity that restricts the efficacy of chimeric antigen receptor (CAR) T cell therapy in solid tumors, with a focus on exploring the epigenetic regulatory mechanisms of CD70—a promising solid tumor target with aberrant overexpression—and developing next-generation CAR-T strategies to overcome CD70 expression heterogeneity. We comprehensively elucidate the epigenetic mechanisms underlying CD70 expression heterogeneity in solid tumors, and verify the core role of EZH2-mediated H3K27me3 modification in silencing CD70 in partial tumor cells and leading to ultra-low CD70 expression undetectable by conventional assays. Meanwhile, we analyze the limitations of conventional CD70-targeted CAR-T cells in solid tumor treatment, and highlight the revolutionary progress of next-generation CAR-T platforms, especially HLA-independent T cell (HIT) receptor technology, which enables the specific recognition and elimination of CD70 ultra-low expressing tumor cells. Additionally, we summarize the current status of preclinical studies and clinical trials of CD70-targeted CAR-T therapies for solid tumors, including efficacy-enhancing strategies such as epigenetic modulation, combined therapy and gene-edited allogeneic CAR-T cells. In conclusion, CD70 is a paradigm-shifting target for solid tumor immunotherapy, and the development of ultra-sensitive next-generation CAR-T platforms represented by HIT receptors has broken through the key obstacle of targeting CD70 ultra-low expressing cells. The integration of epigenetic diagnostic techniques, high-sensitivity CAR-T cells and rational combination therapy strategies will be the key to realizing the curative potential of CD70-targeted therapy, and this therapy is expected to reshape the treatment landscape of CD70-positive solid tumors, while the translation of these technological breakthroughs still faces challenges such as biomarker development, toxicity management and manufacturing scalability that need to be addressed.

Objective: To methodically assess the prognostic predictive value of baseline neutrophil-to-lymphocyte ratio (NLR) in cancer patients receiving immune checkpoint inhibitor (ICI) therapy.

Methods: We conducted a systematic search in PubMed, Embase, Cochrane Library, and Web of Science. The search covered studies from each database's founding to December 31, 2024. We included cohort studies or post hoc analyses from randomized controlled trials that assessed the association between baseline NLR (neutrophil-to-lymphocyte ratio) and the prognosis of ICI (immunotherapy) treatment. The Newcastle-Ottawa Scale, a tool for quality assessment of non-randomized studies, was used. Random-effect models combine effect sizes across studies. Subgroup analysis (examining results within subgroups), meta-regression (statistical exploration of heterogeneity), and sensitivity analysis (testing the robustness of the results) were performed.

Results: Sixty-eight studies, including 18,947 patients, were analyzed. Patients with high NLR (neutrophil-to-lymphocyte ratio) had significantly poorer overall survival (OS, time until death from any cause) compared to those with low NLR (combined HR=1.96, 95% CI: 1.74-2.21, P<0.001). They also had worse progression-free survival (PFS, time until disease worsens or patient dies) (combined HR=1.82, 95% CI: 1.63-2.03, P<0.001). The high NLR group showed lower objective response rate (ORR, proportion of patients with tumor shrinkage) and disease control rate (DCR, proportion of patients with tumor response or stable disease), with combined ORs of 0.42 (95% CI: 0.35-0.51) and 0.53 (95% CI: 0.44-0.64). Subgroup analysis (examining results by groups) showed consistent associations across cancer types, treatment lines, and ICI types. The NLR cutoff value (the threshold used to define high vs. low NLR) was the main source of heterogeneity (P=0.009). Sensitivity analysis (testing the effects of excluding certain studies) supported the robustness of the results.

Conclusion: Elevated baseline NLR is an independent predictor of poor prognosis in cancer patients receiving ICI therapy. As a simple, inexpensive biomarker, NLR can help screen populations that may benefit from ICI treatment.

Cancer immunotherapies have achieved remarkable clinical success, yet their efficacy remains limited in tumors with low immunogenicity and insufficient antigen presentation within the tumor microenvironment. The absence or dysfunction of conventional type 1 dendritic cells (cDC1s)—the key antigen-presenting cells responsible for priming and sustaining cytotoxic T cell responses—represents a critical barrier to effective antitumor immunity. Recent advances in cellular reprogramming have opened new avenues to address this limitation through in vivo conversion of tumor cells themselves into immunogenic cell types. This review summarizes the current state of in vivo reprogramming strategies aimed at enhancing tumor immunogenicity and T cell-mediated immunity. We focus primarily on the pioneering approach of converting tumor cells into cDC1-like cells through adenoviral delivery of the transcription factors PU.1, IRF8, and BATF3 (PIB). This strategy induces profound remodeling of the tumor microenvironment, recruitment and expansion of polyclonal cytotoxic T cells, formation of tertiary lymphoid structures, and establishment of long-term systemic immunity in preclinical models. We discuss the mechanistic basis of this approach, compare it with alternative reprogramming strategies targeting other immune cell lineages, examine the challenges and limitations for clinical translation, and explore future directions for combination therapies. The ability to transform cancer cells from within into allies that orchestrate antitumor immune responses represents a paradigm shift in cancer immunotherapy with the potential to extend benefits to patients who currently fail to respond to existing treatments.